Tissue substitute multilayer matrix and uses thereof

ABSTRACT

Compositions-of-matter comprising a matrix made of one or more, preferably two or more elastic layers and one or more viscoelastic layer are disclosed. The compositions-of-matter are characterized by high water-impermeability and optionally by self-recovery. Processes of preparing the compositions-of-matter and uses thereof as tissue substitutes or for repairing damaged tissues are also disclosed.

This application is a Continuation of U.S. Ser. No. 16/683,620 filed onNov. 14, 2019, which is a Continuation of U.S. Ser. No. 15/102,966 filedon Jun. 9, 2016 and issued as U.S. Pat. No. 10,478,519, which is aNational Phase of PCT Patent Application No. PCT/IL2014/051109 filed onDec. 17, 2014, which claims the benefit of priority of U.S. ProvisionalApplication No. 61/916,829 filed on Dec. 17, 2013. The contents of theabove applications are all incorporated by reference as if fully setforth herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to tissuesubstitutes, and more particularly, but not exclusively, to an elasticlayered matrix and to uses thereof as a tissue substitute.

Leakage of liquid or air from or into damaged tissue is a potentiallylife-threatening condition which may occur as a result of a wide varietyof circumstances, including surgery and traumatic injury.

The dura mater, also referred to herein and in the art simply as “dura”,is a thin membrane that surrounds the brain and spinal cord, and whichis responsible for containment of the cerebrospinal fluid. The duramater may be damaged as a result of traumatic injury or of a surgicaloperation requiring access to underlying nervous tissue (e.g., opencranial neurosurgery, spinal surgery). When the dura mater is damaged, adural substitute in a form of a patch may be needed to prevent leakageof cerebrospinal fluid, prevent infection, and promote tissue regrowth(e.g., dura mater regeneration). Background Art FIG. 8 schematicallydepicts such a use of a dural substitute.

Materials which have been used as dural substitutes include autologoustissue grafts (such as temporal fascia, fascia lata femoris andperiosteal flaps), allografts (such as lyophilized cadaveric duralgrafts), xenografts (such as bovine pericardium and porcine smallintestinal submucosa), and natural and synthetic polymers, such aspoly(lactic acid), poly(ε-caprolactone), expandedpoly(tetrafluoroethylene), polyurethane, poly(ethylene glycol),poly(hydroxyethyl methacrylate), collagen, gelatin, fibrinogen andalginate [Wang et al., J Biomed Mater Res B Applied Biomater 2013,101:1359-1366].

Collagen-based matrices, such as Duragen® matrices and other brandedproducts, have become widely used, as they promote cell ingrowth andtissue integration, and under certain conditions can be implantedwithout sutures by simply being onlaid. The collagen in such matrices istypically animal-derived. However, such matrices exhibit low tensilestrength, frequently leak, and are unsuitable for being sutured ifnecessary [Kurpinski & Patel, Nanomedicine 2011, 6:325-337; Wang et al.,J Biomed Mater Res B Applied Biomater 2013, 101:1359-1366]. Use ofcollagen-based dural substitutes is associated with post-surgicalinfections in 15-20% of patients. The use of additional products, suchas liquid sealants, for overcoming the shortcomings of collagen-basedmatrices can complicate an operation and increase costs.

Kurpinski & Patel [Nanomedicine 2011, 6:325-337] describe a bilayeredsynthetic nanofibrous dura mater substitute fabricated from blendedelectrospun fibers of poly(DL-lactide-co-ε-caprolactone) (in a 70:30ratio) and poly(propylene glycol). The bilayered design comprises analigned nanofiber layer which is reported to promote cell guidance andhealing, and a random nanofiber layer for enhancing mechanicalintegrity. The bilayered structure was formed by electrospinning in amanner such that a single continuous fiber is initially deposited in apredominantly aligned orientation, and later deposited in apredominantly random orientation.

Wang et al. [J Biomed Mater Res B Applied Biomater 2013, 101:1359-1366]describe a dural substitute fabricated by electrospinning, comprising aninner layer composed of poly(lactic acid) for reducing tissue adhesion,a middle layer composed of poly(ε-caprolactone) and poly(lactic acid)for providing water-tightness, and an outer layer comprising collagenfor promoting cell attachment.

U.S. Pat. No. 8,795,708 describes an artificial dura mater comprisingelectrospun layers, including at least one hydrophobic electrospunlayer, and optionally at least one hydrophilic layer. The hydrophobiclayer is intended to be placed proximate to the brain surface to takeadvantage of its anti-adhesion capability, whereas the hydrophilic layeris intended to be placed distant to the brain for serving as a scaffoldfor cells.

U.S. Patent Application Publication No. 2009/0004239 describesmultilayer structures for dural repair, including a porous layer, suchas a collagen containing foam; and a non-porous layer, such as acollagen film, having a reinforcement member, such as a mesh.

U.S. Pat. No. 6,514,291 describes an artificial dura mater comprising atleast one sheet of a synthetic polymer, such as a lactide/ε-caprolactonecopolymer, having a storage elastic modulus of 10⁷ to 5×10⁸ Pa at 37° C.The sheet can be produced by dissolving a lactide/ε-caprolactonecopolymer (in a molar ratio ranging from 40:60 to 60:40) in a solvent,filtering and casting the resultant solution, followed by air drying.Three layer structures comprising a reinforcement synthetic polymersandwiched between two of the aforementioned sheets are also describedtherein.

European Patent No. 1741456 describes an artificial dura matercomprising a laminate of at least two layers, at least one of which isformed of a lactic acid/glycolic acid/ε-caprolactone copolymer having amolar ratio of 60-85% lactic acid, 3-15% glycolic acid, and 10-30%ε-caprolactone.

European Patent No. 2163269 describes an artificial dura matercomprising an amorphous or low-crystallinity polymer, such as acopolymer of L-lactic acid and ε-caprolactone, and a structuralreinforcement. The amorphous or low crystallinity polymer ischaracterized by a low elastic modulus (10⁸ Pa or less at 37° C.) andhigh relaxation elastic modulus (30% or more of the elastic modulus), inorder to prevent leakage after suturing.

U.S. Patent Application Publication No. 2010/0233115 describes a fibrouspolymer scaffold having a first layer of aligned polymer fibers, asecond layer of polymer fibers, and optionally additional layers. Thesecond layer can include unaligned or randomly oriented fibers, orfibers that are aligned and offset from the average axis of alignment ofthe first layer.

Additional background art includes U.S. Patent Application PublicationNo. 2013/0197663.

SUMMARY OF THE INVENTION

Based on information gathered from several resources, includingpracticing surgeons, the present inventors have envisioned that it wouldbe advantageous for a matrix used as a dural substitute to exhibit thefollowing features: a) ability to create a tight seal to preventcerebrospinal fluid leakage; b) mechanical strength sufficient forenabling robust suturing or stapling; c) capability of recovering uponformation of a suture or a staple hole; d) flexibility for conforming tocomplex surfaces without creasing; e) ability to be cut with a simplescissors and in general, easy to handle; f) ability to integrate intoexisting dura mater without adhering to neural tissue; g)biodegradability characterized by a controlled rate of degradation(which balances tissue growth and “creeping” of growing tissue into thematrix); h) ability to enhance damaged tissue regrowth, in order tosupport wound healing and recuperation; i) biocompatibility for reducingor preventing rejection and/or development of local inflammation; and j)ability to reduce risk of bacterial or viral infection. Such propertieswould overcome many shortcomings of existing dural substitutes.

According to an aspect of some embodiments of the present inventionthere is provided a composition-of-matter comprising a multi-layermatrix, the matrix comprising at least one layer of an elastic polymericmaterial and at least one layer of a viscoelastic polymeric material.

According to some embodiments, the matrix contains two of the layers ofan elastic polymeric material, and one of the layers of a viscoelasticpolymeric material interposed between the layers of an elastic polymericmaterial.

According to an aspect of some embodiments of the present inventionthere is provided a composition-of-matter comprising a multi-layermatrix, the matrix comprising at least two layers of an elasticpolymeric material and at least one layer of a viscoelastic polymericmaterial interposed between two of the layers of an elastic polymericmaterial.

According to an aspect of some embodiments of the present inventionthere is provided a multi-layer matrix comprising at least one layer ofan elastic polymeric material and at least one layer of a viscoelasticpolymeric material, the matrix being characterized by awater-permeability of less than 1 ml per hour per cm² upon exposure toan aqueous liquid at a pressure of 40 mmHg.

According to some of any of the embodiments and/or aspect of the presentinvention, a layer of the viscoelastic polymeric material comprises apolymer characterized by a glass transition temperature and/or meltingpoint at a temperature below 40° C.

According to some of any of the embodiments and/or aspect of the presentinvention, one or more of the layers of the elastic polymeric materialis in a form of a porous layer of polymeric fibers, and/or is made ofpolymeric fibers.

According to some embodiments, each of the layers of an elasticpolymeric material is independently made of polymeric fibers.

According to some of any of the embodiments of the present invention,one or more, or each of the layers of the elastic polymeric material ischaracterized by porosity higher than 50%, as defined herein.

According to some of any of the embodiments of the present invention,one or more, or each of the layers of the elastic polymeric material ischaracterized by a porosity higher than 50%, as defined herein, and theone or more layers of the viscoelastic polymeric material ischaracterized by a lower porosity, e.g., lower than 50% or lower than30%, or lower than 20%, or lower than 10%, or even as non-porous.

According to some of any one of the embodiments and/or aspect of thepresent invention, at least two layers of the elastic polymericmaterial, each of the layers is independently in a form of a porouslayer of polymeric fibers, wherein the layer of a viscoelastic polymericmaterial is interposed between two of the layers of an elastic polymericmaterial.

According to some of any one of the embodiments and/or aspect of thepresent invention, the elastic polymeric material comprises a polymercharacterized by a glass transition temperature and/or melting point ata temperature above 40° C.

According to some embodiments of the present invention there is provideda composition-of-matter comprising a multi-layer matrix, the matrixcomprising at least one layer of an elastic polymeric material and atleast one layer of a viscoelastic polymeric material, wherein each ofsaid viscoelastic polymeric material and the elastic polymeric materialindependently comprises a polymer characterized by a glass transitiontemperature and/or melting point at a temperature above 40° C.

According to some of any of the embodiments and/or aspects of thepresent invention, the layer of a viscoelastic polymeric material ischaracterized by a loss tangent (G″/G′) at a temperature of 10° C. andfrequency of 0.1 Hz which is in a range of from 0.01 to 4.

According to some of any of the embodiments and/or aspects of thepresent invention, one or more of, or each layer of the elasticpolymeric material is a porous layer characterized by a porosity of atleast 50%.

According to some of any of the embodiments and/or aspects of thepresent invention, the polymeric fibers are characterized by a meandiameter in a range of from 0.001 to 30 μm.

According to some of any of the embodiments and/or aspects of thepresent invention, the layer of a viscoelastic polymeric material ischaracterized by at least one of:

a) a storage shear modulus (G′) in a range of from 0.01 to 10 MPa, at atemperature of 10° C. and frequency of 0.1 Hz; and

b) a loss shear modulus (G″) in a range of from 0.0001 to 2 MPa, at atemperature of 10° C. and frequency of 0.1 Hz.

According to some of any of the embodiments and/or aspects of thepresent invention, the matrix is characterized by a thickness of lessthan 3 mm.

According to some of any of the embodiments and/or aspects of thepresent invention, a layer of the polymeric fibers is characterized by athickness in a range of from 10 to 500 μm.

According to some of any of the embodiments and/or aspects of thepresent invention, the polymeric fibers comprise electrospun elasticpolymeric material.

According to some of any of the embodiments and/or aspects of thepresent invention, the matrix is characterized by an elastic moduluswhich is similar (+/−20%) to the elastic modulus of the later of theelastic polymeric material.

According to an aspect of some embodiments of the present inventionthere is provided a composition-of-matter comprising a multi-layermatrix, the matrix comprising at least one layer of an elastic polymericmaterial and at least one layer of a viscoelastic polymeric material,wherein a layer of the viscoelastic polymeric material is characterizedby a loss tangent (G″/G′) at a temperature of 10° C. and frequency of0.1 Hz which is in a range of from 0.01 to 4.

According to an aspect of some embodiments of the present inventionthere is provided a composition-of-matter comprising a multi-layermatrix, the matrix comprising at least one layer of an elastic polymericmaterial and at least one layer of a viscoelastic polymeric material,wherein a layer of the viscoelastic polymeric material is characterizedby a loss tangent (G″/G′) at a temperature of 10° C. and frequency of0.1 Hz which is in a range of from 0.01 to 4, and wherein the at leastone layer of an elastic polymeric material is a porous layercharacterized by a porosity of at least 50%.

According to some of any of the embodiments and/or aspects of thepresent invention, the at least one layer of an elastic polymericmaterial comprises polymeric fibers, as described herein.

According to some of any of these embodiments of the present invention,at least one layer of the viscoelastic polymeric material is interposedbetween two layers of the elastic polymeric material.

According to some of any of these embodiments of the present invention,the matrix contains two of the layers of an elastic polymeric material,and one of the layers of a viscoelastic polymeric material interposedbetween the layers of an elastic polymeric material.

According to some of any of these embodiments of the present invention,the layer of a viscoelastic polymeric material is characterized by atleast one of: a) a storage shear modulus (G′) in a range of from 0.01 to10 MPa, at a temperature of 10° C. and frequency of 0.1 Hz; b) a lossshear modulus (G″) in a range of from 0.0001 to 2 MPa, at a temperatureof 10° C. and frequency of 0.1 Hz; and c) a glass transition temperatureand/or melting point of the viscoelastic polymeric material which is ata temperature below 40° C.

According to some of any of the embodiments and/or aspects of thepresent invention, the layer of a viscoelastic polymeric material ischaracterized by a thickness in a range of from 1 to 300 μm.

According to some of any of the embodiments and/or aspects of thepresent invention, the layer of a viscoelastic polymeric material ischaracterized by porosity in a range of from 0 to 50%.

According to some of any of the embodiments and/or aspects of thepresent invention, the elastic polymeric material is biocompatible.

According to some of any of the embodiments and/or aspects of thepresent invention, each of the elastic polymeric material and theviscoelastic polymeric material is made of a biocompatible andbiodegradable polymer. Alternatively one or both polymeric materials arenon-degradable.

According to some of any of the embodiments and/or aspects of thepresent invention, the matrix is characterized by a thickness of lessthan 3 mm.

According to some of any of the embodiments and/or aspects of thepresent invention, each of the layers of an elastic polymeric materialis characterized by a thickness in a range of from 10 to 500 μm.

According to some of any of the embodiments and/or aspects of thepresent invention, the elastic polymeric material comprises a polymercharacterized by a glass transition temperature and/or melting point ata temperature above 40° C.

According to some of any of the embodiments and/or aspects of thepresent invention, one or more of, or each of the layers of an elasticpolymeric material is characterized by an elastic modulus in a range offrom 1 kPa to 1 GPa.

According to some of any of the embodiments and/or aspects of thepresent invention, one or more of, or each of the layers of an elasticpolymeric material is characterized by an elongation at failure of atleast 100%.

According to some of any of the embodiments and/or aspects of thepresent invention, one or more of, or each of the layers of an elasticpolymeric material is characterized by an ultimate tensile strength ofat least 0.05 MPa.

According to some of any of the embodiments and/or aspects of thepresent invention, one or more of, or each of the layers of an elasticpolymeric material is characterized by a recovery of at least 75%.

According to some of any of the embodiments and/or aspects of thepresent invention, the matrix is characterized by an elastic moduluswhich is within a range of 80% to 120% of an elastic modulus of at leastone of the elastic layers.

According to some of any of the embodiments and/or aspects of thepresent invention, the one or more layers of an elastic polymericmaterial are each independently formed of a polymeric material selectedfrom the group consisting of a polyester, a polyanhydride, a polyacetal,a polyorthoester, a polyurethane, a polycarbonate, a polyphosphazene, apolyphosphoester, a polyether, a silicone, a polyamide, a polysulfone, apolyether ether ketone (PEEK), poly(ethylene glycol),polytetrafluoroethylene, polyethylene, poly(methyl methacrylate),poly(ethyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), apolypeptide, a polysaccharide and copolymers thereof.

According to some of any of the embodiments and/or aspects of thepresent invention, the polyester is selected from the group consistingof poly(lactic acid), poly(ε-caprolactone), poly(glycolic acid),poly(trimethylene carbonate), poly(ethylene terephthalate),polydioxanone and copolymers thereof.

According to some of any of the embodiments and/or aspects of thepresent invention, the polypeptide is selected from the group consistingof collagen, alginate, elastin, an elastin-like polypeptide, albumin,fibrin, chitosan, silk, poly(γ-glutamic acid) and polylysine.

According to some of any of the embodiments and/or aspects of thepresent invention, at least one of the layers of an elastic polymericmaterial comprises an electrospun polymeric material.

According to some of any of the embodiments and/or aspects of thepresent invention, the viscoelastic polymeric material comprisespoly(lactic acid-co-ε-caprolactone).

According to some of any of the embodiments and/or aspects of thepresent invention, the viscoelastic polymeric material is characterizedby a glass transition temperature and/or melting point at a temperaturewhich is at least 5° C. lower than an ambient temperature of thecomposition-of-matter.

According to some of any of the embodiments and/or aspects of thepresent invention, the layer of a viscoelastic polymeric material ischaracterized by a storage shear modulus (G′) in a range of from 0.01 to10 MPa, at a temperature of 10° C. and frequency of 0.1 Hz.

According to some of any of the embodiments and/or aspects of thepresent invention, the layer of a viscoelastic polymeric material ischaracterized by a loss shear modulus in a range of from 0.0001 to 2MPa, at a temperature of 10° C. and frequency of 0.1 Hz.

According to an aspect of some embodiments of the present inventionthere is provided a composition-of-matter comprising a multi-layermatrix, the matrix comprising at least one layer of an elastic polymericmaterial and at least one layer of a viscoelastic polymeric material,

wherein the layer of a viscoelastic polymeric material is characterizedby at least one of: a) a storage shear modulus (G′) in a range of from0.01 to 10 MPa, at a temperature of 10° C. and frequency of 0.1 Hz; b) aloss shear modulus (G″) in a range of from 0.0001 to 2 MPa, at atemperature of 10° C. and frequency of 0.1 Hz; c) a glass transitiontemperature and/or melting point of the viscoelastic polymeric materialwhich is at a temperature below 40° C.; and d) a loss tangent (G″/G′) ata temperature of 10° C. and frequency of 0.1 Hz which is in a range offrom 0.01 to 4, and wherein the layer of an elastic polymeric materialis characterized by at least one of: a) an elastic modulus in a range offrom 1 kPa to 1 GPa; b) an elongation at failure in a range of at least100%; and c) a glass transition temperature and/or melting point of theelastic polymeric material which is at a temperature above 40° C.

According to an aspect of some embodiments of the present invention,there is provided a composition-of-matter comprising a multi-layermatrix, the matrix comprising at least one layer of an elastic electrospun polymeric material and at least one layer of a viscoelasticpolymeric material, wherein: the elastic polymeric material is selectedfrom the group consisting of poly(lactic acid-co-ε-caprolactone),poly(ε-caprolactone-co-L-lactic acid-co-glycolic acid-co-trimethylenecarbonate), mixtures of poly(lactic acid-co-ε-caprolactone) andpoly(lactic acid), and mixtures of poly(ε-caprolactone-co-L-lacticacid-co-glycolic acid-co-trimethylene carbonate) and poly(lactic acid),and the viscoelastic polymeric material is poly(lacticacid-co-ε-caprolactone).

According to some of any of the embodiments and/or aspects of thepresent invention, a matrix as described herein is characterized by awater-permeability of less than 1 ml per hour per cm² upon exposure toan aqueous liquid at a pressure of 40 mmHg.

According to an aspect of some embodiments of the present inventionthere is provided a layered matrix, characterized by awater-permeability of less than 1 ml per hour per cm² upon exposure toan aqueous liquid at a pressure of 40 mmHg.

According to some embodiments, the matrix is a layered matrix comprisingat least one layer of an elastic polymeric material and at least onelayer of a viscoelastic polymeric material.

According to some embodiments, the matrix is any one of the matricesdescribed herein, in any one of the respective embodiments and anycombination thereof.

According to some of any of the embodiments and/or aspects of thepresent invention, any of the compositions-of-matter described hereinfurther comprises at least one additional ingredient, the additionalingredient being in a form of an additional layer on at least a portionof at least one surface of the matrix and/or dispersed within and/or onat least one surface of the matrix, the at least one additionalingredient imparting an additional functionality.

According to some embodiments of the present invention, the additionalfunctionality is selected from the group consisting ofwater-impermeability, inhibition of formation of an adhesion to tissue,reduction of risk of infection, tissue rejection and/or immune response,and adhesion to tissue without suturing.

According to some embodiments of the present invention, the additionalingredient is selected from the group consisting of an adhesivematerial, a non-adhesive material, hydrophobic polymer particles, abiological and/or bio-active material, a growth factor, and atherapeutically effective agent.

According to some embodiments of the present invention, the additionallayer is selected from the group consisting of a water-impermeablelayer, a tissue-adhesive layer, a cell growth-promoting layer and ananti-fouling layer.

According to an aspect of some embodiments of the present inventionthere is provided a suturable and/or stapleable matrix capable ofself-recovery, as defined herein. According to some embodiments, thematrix is any one of the matrices described herein, in any one of therespective embodiments and any combination thereof.

According to an aspect of some embodiments of the present inventionthere is provided an article-of-manufacture comprising any of thecompositions-of-matter or matrices as described herein, in any one ofthe embodiments thereof and any combination of these embodiments.

According to some embodiments of the present invention, thearticle-of-manufacture of is a medical device, for example, animplantable medical device and/or a tissue substitute.

According to some of any of the embodiments of the present invention,the article-of-manufacture is identified for use in repairing tissuedamage.

According to some embodiments of the present invention, the tissue isselected from the group consisting of dura mater, brain tissue, retina,skin tissue, hepatic tissue, pancreatic tissue, bone, cartilage,connective tissue, blood tissue, muscle tissue, cardiac tissue, vasculartissue, renal tissue, pulmonary tissue, gonadal tissue, hematopoietictissue and fat tissue.

According to some of any of the embodiments of the present invention,the article-of-manufacture is identified for use in a treatment selectedfrom the group consisting of dural repair, hernia repair, internaland/or topical wound closure, skin closure and/or repair, sealingtissues and/or organs in order to contain bodily fluids or air, sealingan anastomosis, inhibition of post-surgical adhesions between tissues,promotion of hemostasis, and administration of a therapeuticallyeffective agent.

According to some of any of the embodiments of the present invention,the article-of-manufacture is for use in repairing and/or substituting abiological tissue.

According to an aspect of some embodiments of the present inventionthere is provided a method of repairing and/or substituting a biologicaltissue in a subject in need thereof, the method comprising contactingthe biological tissue with the article-of-manufacture as described inany one of the embodiments thereof, thereby repairing and/orsubstituting the biological tissue.

According to some of any of the embodiments of the present invention,the biological tissue is a membrane.

According to some of any of the embodiments of the present invention,the membrane is dura mater.

According to some of any of the embodiments of the present invention,the biological tissue in any of the tissues described herein.

According to some of any of the embodiments of the present invention,the biological tissue the repairing and/or substituting a biologicaltissue comprises suturing and/or stapling the article-of-manufacture tothe tissue.

According to an aspect of some embodiments of the present inventionthere is provided a process for preparing the composition-of-matter asdescribed herein, the process comprising forming the layers of anelastic polymeric material and the at least one layer of a polymericviscoelastic layer by continuous electrospinning.

According to an aspect of some embodiments of the present inventionthere is provided a process for preparing the composition-of-matter asdescribed herein, the process comprising forming the layers of anelastic polymeric material by electrospinning, placing the at least onelayer of a viscoelastic polymeric material parallel to the layers of anelastic polymeric material, and pressing the layers of an elasticpolymeric material and the at least one layer of a viscoelasticpolymeric material together, thereby forming the composition-of-matter.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings and images.With specific reference now to the drawings and images in detail, it isstressed that the particulars shown are by way of example and forpurposes of illustrative discussion of embodiments of the invention. Inthis regard, the description taken with the drawings and images makesapparent to those skilled in the art how embodiments of the inventionmay be practiced.

In the drawings:

FIG. 1 is a scheme of an electrospinning apparatus for preparingelectrospun materials according to some embodiments of the invention,showing a syringe filled with polymer solution placed at a fixeddistance from an electrically grounded metal rotating collector, and ahigh-voltage DC generator connected to the needle of the syringe, forgenerating a strong electromagnetic field (over 5 kV) which draws fibersfrom the solution onto the collector; the polymer solution is driven outof the syringe at a steady rate by a syringe pump (not shown);

FIG. 2 is a scheme showing the structure of a 3-layer patch according tosome embodiments of the invention;

FIGS. 3A-3D present scanning electron microscopy (SEM) images of thefibers of an exemplary elastic layer according to some embodiments ofthe invention;

FIGS. 4A and 4B present SEM images of a cross-section of an exemplary3-layer patch according to some embodiments of the invention (borders ofthe viscoelastic layer indicated in FIG. 4B by vertical white lines);

FIGS. 5A-5F present SEM images of a puncture formed by a suture needle(FIGS. 5A and 5B, circle in FIG. 5A indicates location of puncture), amonofilament suture (FIG. 5C) and braided suture (FIG. 5D) in anexemplary 3-layer patch according to some embodiments of the invention,and a cross-section of the 3-layer patch (FIGS. 5E and 5F) (whiterectangle in FIG. 5F shows higher magnification, borders of theviscoelastic layer indicated by vertical white lines);

FIGS. 6A-6C present SEM images of a cross-section of an exemplary3-layer patch according to some embodiments of the invention (borders ofthe viscoelastic layer indicated in FIGS. 6B and 6C by vertical whitelines);

FIG. 7 is a bar graph showing the leakage of saline (meanvolume±standard error of mean) over the course of 30 minutes atpressures of 15 or 40 mmHg through exemplary single layers, doubleelastic layers, and 3-layer patches prepared by continuouselectrospinning (ES) or by pressing 3 sheets together (LBL), accordingto some embodiments of the invention, and 3-layer patches prepared bypressing 3 sheets together and containing a suture hole with suture inthe hole, as well as leakage through collagen dural substitutes (forcollagen dural substitutes, 50 ml of saline leaked through in less than5 minutes); and

FIG. 8 (Background Art) is a scheme showing a breach in dura mater andskull before (left) and after (middle) closure of the breached duramater with a commercially available dural substitute (thin green line)and closure of the breached skull (thick green line) (3-dimensionaldepiction of application of dural substitute on right).

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to tissuesubstitutes, and more particularly, but not exclusively, to an elasticlayered matrix and to uses thereof as a tissue substitute.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details of construction and the arrangement of thecomponents and/or methods set forth in the following description and/orillustrated in the drawings and/or the Examples. The invention iscapable of other embodiments or of being practiced or carried out invarious ways.

Current biocompatible matrices and technologies for tissue repair, suchas dural substitutes, do not provide a desirable mechanical strength,flexibility and impermeability to biological fluids (such ascerebrospinal fluid) and pathogens. In particular, the widespread use ofsutures and/or staples to hold a matrix in place can be particularlydetrimental to the impermeability and mechanical strength and integrityof matrices, due to the formation of holes in the matrix.

The present inventors have uncovered matrices which can exhibit adesired degree of biocompatibility, mechanical strength, flexibilityand/or impermeability, and furthermore, can respond to punctures such asthose formed by suturing or stapling in a manner which limits thedetrimental effects thereof.

Referring now to the drawings, FIG. 1 schematically depicts theformation of a layer of fibers by electro spinning. Elastic layersand/or viscoelastic layers may optionally be formed by such a technique.

FIG. 2 depicts a 3-layer patch according to some embodiments of theinvention, wherein a viscoelastic layer is sandwiched between twoelastic layers. FIGS. 3A-3D show exemplary elastic layers formed fromelectrospun fibers. FIGS. 4A, 4B, 5E, 5F and 6A-6C show exemplary3-layer patches, wherein a viscoelastic layer is sandwiched between twoelastic layers.

FIGS. 5A-5D show that suture holes formed in an elastic layer of anexemplary 3-layer patch are effectively closed, in the presence orabsence of the suture. FIG. 7 shows that exemplary 3-layer patches arehighly water-impermeable, even when sutured, and that the viscoelasticlayer contributes significantly to this water-impermeability.

Embodiments of the present invention relate to liquid-impermeablelayered matrices which exhibit a unique combination of mechanical andrheological properties and to uses thereof in a variety of medicalapplications, and specifically, but not exclusively, as implants, andparticularly as tissue substitutes such as, but not limited to, durasubstitutes. Embodiments of the present invention further relate torecoverable matrices, which upon being subjected to suturing orstapling, self-recover so as to seal the holes formed by suchprocedures.

The layered matrices provided herein comprise two or layers, each madeof a polymeric material, wherein one or more of these layers exhibithigh elasticity and additional, one or more layers exhibit highviscoelasticity.

As exemplified herein, layered matrices such as described herein (alsoreferred to herein as “patches”) can be formed from biodegradable andbiocompatible materials, while exhibiting considerable mechanicalstrength, a high degree of elasticity and flexibility, ease of handling,an ability to be folded (as may be useful for laparoscopic surgicalprocedures) without permanent deformation (e.g., without creasing), lowdensity (which may decrease inflammation and infection), and a highdegree of water-impermeability suitable for creating a tight seal,preventing fluid leakage, and preventing bacterial and viral infections.

The Matrix:

According to an aspect of some embodiments of the invention, there isprovided a composition-of-matter comprising a multi-layer matrix, thematrix comprising one or more elastic layers and at least oneviscoelastic layer. In some such embodiments, the matrix comprises atleast two elastic layers. In exemplary embodiments, the matrix comprisestwo elastic layers and one viscoelastic layer interposed between theelastic layers.

As used herein, the term “composition-of-matter” includes a matrix whichis also referred to herein interchangeably as a “core matrix”, and mayoptionally further include additional components, ingredients and/orlayers as described herein, according to any of the respectiveembodiments.

As used herein, the term “multi-layer” refers to a presence of at leasttwo distinct layers. The distinct layers may differ, for example, inchemical composition, molecular configuration (e.g., degree and type ofcrystallinity), physical structure and/or mechanical properties.

Herein, the term “matrix” (including “core matrix”), when used in thecontext of a composition-of-matter comprising a multi-layer matrix asdescribed herein, refers to the one or more elastic layers andviscoelastic layers (as described herein, according to any of therespective embodiments) and further includes any materials incorporatedwithin and/or interposed between the elastic and/or viscoelastic layers.That is, the matrix does not include any component of thecomposition-of-matter which is outside of (i.e., neither within norbetween) the elastic and viscoelastic layers.

In some embodiments of any one of the embodiments described herein, thematrix is defined by elastic layers (as described herein, according toany of the respective embodiments) and includes any materials(including, but not limited to, a viscoelastic layer according to any ofthe respective embodiments described herein) incorporated within and/orinterposed between the elastic layers. That is, the core matrix does notinclude any component of the composition-of-matter which is outside ofthe elastic layers.

As used herein, the phrase “elastic layer” refers to a layer ofmaterial, wherein the layer exhibits elasticity.

Herein, the terms “elasticity” and “elastic” refer to a tendency of amaterial (optionally in a form of a layer) to return to its originalshape after being deformed by stress, for example, a tensile stressand/or shear stress, at an indicated temperature or at a temperature of37° C. (in contexts wherein no temperature is indicated).

As used herein, the phrase “viscoelastic layer” refers to a layer ofmaterial, wherein the layer exhibits viscoelasticity.

Herein, the terms “viscoelasticity” and “viscoelastic” refer to atendency of a material (optionally in a form of a layer) to resiststress to a degree which correlates with the rate of deformation (e.g.,strain, shear), at an indicated temperature or at a temperature of 37°C. (in contexts wherein no temperature is indicated). That is, whendeformation is effected relatively slowly, the resistance of thematerial is lower (e.g., due to viscous flow during deformation), andthe resistance may optionally approach zero as the rate of deformation(e.g., shear) approaches zero. The resistance will typically not besufficient to allow the material to return to its original shape, exceptin some cases wherein the rate of deformation is very high.

A degree of viscoelasticity may optionally be characterized by a losstangent (G″/G′), which is a ratio of a loss shear modulus (G″, alsoreferred to herein interchangeably as a “shear loss modulus”) to storageshear modulus (G′, also referred to herein interchangeably as a “shearstorage modulus”). A loss shear modulus reflects viscous behavior,whereas a storage shear modulus reflects elastic behavior.

In some embodiments, of any one of the embodiments described herein, aviscoelastic material (e.g., viscoelastic layer) is characterized inthat a loss tangent of at least 0.01.

In some embodiments, of any one of the embodiments described herein, theviscoelastic layer is characterized by a loss tangent which is greaterthan a loss tangent of the elastic layer. In some embodiments, aviscoelastic layer is characterized by a loss tangent which is at least200% of (two-fold) a loss tangent of the elastic layer.

Storage shear modulus and loss shear modulus may optionally bedetermined using a shear rheometer, for example, a strain-controlledrotational rheometer, at an indicated temperature and frequency (e.g.,using procedures described in the Examples section herein).

The elastic and viscoelastic layers described herein are preferably madeof a polymeric material selected to exhibit the elasticity and/orviscoelasticity according to any of the respective embodiments describedherein. A person skilled in the art would recognize which polymericmaterials (e.g., polymers and mixtures thereof) to select, and how toproduce a layer therefrom in order to obtain a layer exhibiting theindicated features (e.g., elasticity and/or viscoelasticity) withoutundue experimentation, particularly in view of the description andguidance provided herein.

Herein, in embodiments wherein an elastic layer is made of a polymericmaterial, the phrase “elastic layer” and “layer of an elastic polymericmaterial” are used interchangeably.

Herein, in embodiments wherein a viscoelastic layer is made of apolymeric material, the phrase “viscoelastic layer” and “layer of aviscoelastic polymeric material” are used interchangeably.

In some embodiments of any one of the embodiments described herein, thematrix contains one layer of viscoelastic material.

The elastic layer(s) and viscoelastic layer(s) may be layered in anyorder. An elastic layer may optionally be adjacent to (e.g., in directcontact with) a viscoelastic layer and/or another elastic layer, and aviscoelastic layer may optionally be adjacent to (e.g., in directcontact with) an elastic layer and/or another viscoelastic layer. Insome embodiments of any one of the embodiments described herein, thematrix comprises at least one viscoelastic layer between the elasticlayers (according to any of the respective embodiments describedherein). Such a configuration includes, for example, more than oneviscoelastic layer between a pair of elastic layers, and one or moreelastic layers which, along with the viscoelastic layer(s), areinterposed between other elastic layers.

As used herein, a material (e.g., viscoelastic layer) which is “between”layers (e.g., elastic layers) is located in at least a portion of theregion between the layers, and does not exclude other substances fromalso being between the layers, and optionally is not in contact with oneor more of the layers.

Without being bound by any particular theory, it is believed that alocation of a viscoelastic polymeric material between elastic layers,allows the elastic layers to contain the viscoelastic polymeric materialwithin the matrix, and prevent significant leaching of the viscoelasticpolymeric material. It is further believed that a viscoelastic polymericmaterial is in a form of an intermediate layer is highly suitable foracting as a barrier and for closing holes, as described herein, whilebeing effectively contained by the elastic layers.

In some embodiments of any one of the embodiments described herein, thecore matrix contains two elastic layers as described herein (accordingto any of the respective embodiments) and one viscoelastic layer asdescribed herein (according to any of the respective embodiments)interposed between the two elastic layers.

Herein, the term “polymeric material” (including within the phrases“elastic polymeric material” and “viscoelastic polymeric material”)refer to a material comprising one or more polymers (as defined herein),wherein at least 20 weight percents (by dry weight) of the materialconsists of the one or more polymers.

In some embodiments of any of the embodiments described herein, at least30 weight percents (by dry weight) of the polymeric material (e.g.,elastic polymeric material and/or viscoelastic polymeric material)consists of one or more polymers. In some embodiments, at least 40weight percents (by dry weight) of the polymeric material consists ofone or more polymers. In some embodiments, at least 50 weight percents(by dry weight) of the polymeric material consists of one or morepolymers. In some embodiments, at least 60 weight percents (by dryweight) of the polymeric material consists of one or more polymers. Insome embodiments, at least 70 weight percents (by dry weight) of thepolymeric material consists of one or more polymers. In someembodiments, at least 80 weight percents (by dry weight) of thepolymeric material consists of one or more polymers. In someembodiments, at least 90 weight percents (by dry weight) of thepolymeric material consists of one or more polymers. In someembodiments, the polymeric material (e.g., elastic polymeric materialand/or viscoelastic polymeric material) consists essentially of one ormore polymers.

The term “polymer”, as used herein, encompasses organic and inorganicpolymer and further encompasses one or more of a polymer, a copolymer ora mixture thereof (a blend). Polymers used in embodiments of theinvention may be synthetic and/or natural (e.g., biological) in origin.

Non-limiting examples of polymers which are suitable for use in elasticand/or viscoelastic polymeric materials described herein includehomo-polymers and co-polymers such as polyesters (e.g., poly(ethyleneterephthalate) and aliphatic polyesters made of glycolide (glycolicacid), lactide (lactic acid, including L-lactic acid and/or D-lacticacid), ε-caprolactone, dioxanone (e.g., p-dioxanone), trimethylenecarbonate, hydroxybutyrate and/or hydroxyvalerate); polypeptides made ofnatural and/or modified amino acids (e.g., collagen, alginate, elastin,elastin-like polypeptides, albumin, fibrin, chitosan, silk,poly(γ-glutamic acid) and polylysine); polyethers, such as syntheticpolyethers (e.g., poly(ethylene glycol)); polysaccharides made ofnatural and/or modified saccharides (e.g., hyaluronic acid);polydepsipeptides; biodegradable nylon co-polyamides; polydihydropyrans;polyphosphazenes; poly(orthoesters); poly(cyanoacrylates);polyanhydrides; polyurethanes; polycarbonates; silicones; polyamides(e.g., nylons); polysulfones; polyether ether ketones (PEEKs);polytetrafluoroethylene; polyethylene; and polyacrylate esters (e.g.,poly(methyl methacrylate), poly(ethyl methacrylate), poly(methylacrylate) and poly(ethyl acrylate)); any copolymer thereof (includingany ratio of the respective monomers) and any combination thereof.

While any polymer, copolymer or a mixture of polymers and/or copolymerscan be used for producing the elastic and/or viscoelastic polymericmaterial described herein, according to some embodiments of any one ofthe embodiments described herein relating to elastic and/or viscoelasticpolymeric material, the elastic and/or viscoelastic polymeric materialis formed of a biocompatible and/or biodegradable polymer.

In some embodiments, the elastic polymeric material, fibers formed fromthe elastic polymeric material and/or viscoelastic polymeric materialdescribed herein are biocompatible and biodegradable.

In some embodiments, the elastic polymeric material, fibers formed fromthe elastic polymeric material and/or viscoelastic polymeric materialdescribed herein are biocompatible and non-biodegradable.

As used herein, the term “biocompatible” refers to a material which theskilled practitioner would expect the body to generally accept withoutsignificant toxicity, immune response and/or rejection, or excessivefibrosis. In some embodiments, a moderate degree of immune responseand/or fibrosis may optionally be acceptable or desired.

The term “biodegradable” as used in the context of the presentinvention, describes a material which can decompose under physiologicaland/or environmental conditions into breakdown products. Suchphysiological and/or environmental conditions include, for example,hydrolysis (decomposition via hydrolytic cleavage), enzymatic catalysis(enzymatic degradation), and mechanical interactions. This termtypically refers to substances that decompose under these conditionssuch that 30 weight percent of the substance decompose within a timeperiod shorter than one year.

The term “biodegradable” as used in the context of the presentinvention, also encompasses the term “bioresorbable”, which describes asubstance that decomposes under physiological conditions to break downto products that undergo bioresorption into the host-organism, namely,become metabolites of the biochemical systems of the host-organism.

It is expected that during the life of a patent maturing from thisapplication many relevant biocompatible and/or biodegradable polymerswill be developed and the scope of the terms “biocompatible” and“biodegradable” is intended to include all such new technologies apriori.

Preferred biodegradable polymers according to the present embodimentsare non-toxic and benign biocompatible polymers. In some suchembodiments, the biodegradable polymer is a bioresorbable polymers whichdecomposes into non-toxic and benign breakdown products that areabsorbed in the biochemical systems of the subject.

Non-limiting examples of biodegradable polymers which are suitable foruse in elastic and/or viscoelastic polymeric materials described hereininclude homo-polymers and co-polymers such as aliphatic polyesters madeof glycolide (glycolic acid), lactide (lactic acid, including L-lacticacid and/or D-lactic acid), ε-caprolactone, dioxanone (e.g.,p-dioxanone), trimethylene carbonate, hydroxybutyrate and/orhydroxyvalerate; polypeptides made of natural and/or modified aminoacids (e.g., collagen, alginate, elastin, elastin-like polypeptides,albumin, fibrin, chitosan, silk, poly(γ-glutamic acid) and polylysine);polysaccharides made of natural and/or modified saccharides (e.g.,hyaluronic acid); polydepsipeptides; biodegradable nylon co-polyamides;polydihydropyrans; polyphosphazenes; poly(orthoesters);poly(cyanoacrylates); polyanhydrides; copolymers thereof (including anyratio of the respective monomers); and any combination thereof.

Non-limiting examples of non-biodegradable polymers which are suitablefor use in elastic and/or viscoelastic polymeric materials describedherein include polyurethanes, polycarbonates, silicones, polyamides(e.g., nylons), polysulfones, polyether ether ketones (PEEKs),polytetrafluoroethylene, polyethylene, poly(methyl methacrylate),poly(ethyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate)and non-biodegradable polyesters such as, for example, poly(ethyleneterephthalate).

In some embodiments of any one of the embodiments described herein, anyone or more of the elastic and viscoelastic layers is made of polymerfibers. In some embodiments, the fibers are electrospun fibers.

The term “fiber”, as used herein, describes a class of structuralelements, similar to pieces of thread, that are made of continuousfilaments and/or discrete elongated pieces.

In some embodiments of any one of the embodiments described herein, thematrix has a sheet-like geometry. In some embodiments, both thecomposition-of-matter and the matrix have a sheet-like geometry.

In some embodiments of any one of the embodiments described herein, thesheet-like geometry is characterized in that a mean thickness in onedimension (e.g., a mean width in the dimension in which the matrix isnarrowest) is less than 20% of a mean width in each of two perpendiculardimensions. In some such embodiments, a mean thickness in one dimensionis less than 10% of a mean width in each of two perpendiculardimensions. In some such embodiments, a mean thickness in one dimensionis less than 5% of a mean width in each of two perpendicular dimensions.In some such embodiments, a mean thickness in one dimension is less than2% of a mean width in each of two perpendicular dimensions. In some suchembodiments, a mean thickness in one dimension is less than 1% of a meanwidth in each of two perpendicular dimensions. In some such embodiments,a mean thickness in one dimension is less than 0.5% of a mean width ineach of two perpendicular dimensions. In some such embodiments, a meanthickness in one dimension is less than 0.2% of a mean width in each oftwo perpendicular dimensions. In some such embodiments, a mean thicknessin one dimension is less than 0.1% of a mean width in each of twoperpendicular dimensions.

In some embodiments of any one of the embodiments described herein, thematrix is characterized by a mean thickness of less than 3 mm (e.g.,between 60 μm and 3 mm). In some such embodiments, the mean thickness isless than 2 mm (e.g., between 60 μm and 2 mm). In some such embodiments,the mean thickness is less than 1.5 mm (e.g., between 60 μm and 1.5 mm).In some such embodiments, the mean thickness is less than 1.25 mm (e.g.,between 60 μm and 1.25 mm). In some such embodiments, the mean thicknessis less than 1 mm (e.g., between 60 μm and 1 mm). In some suchembodiments, the mean thickness is less than 750 μm (e.g., between 60and 750 μm). In some such embodiments, the mean thickness is less than500 μm (e.g., between 60 and 500 μm). In some such embodiments, the meanthickness is less than 250 μm (e.g., between 60 and 250 μm).

In some embodiments of any one of the embodiments described herein, amean total thickness of the elastic layers is at least 50% (e.g., from50 to 99%) of the mean thickness of the matrix. In some suchembodiments, a mean total thickness of the elastic layers is at least60% (e.g., from 60 to 99%) of the mean thickness of the matrix. In somesuch embodiments, a mean total thickness of the elastic layers is atleast 70% (e.g., from 70 to 99%) of the mean thickness of the matrix. Insome such embodiments, a mean total thickness of the elastic layers isat least 80% (e.g., from 80 to 99%) of the mean thickness of the matrix.In some such embodiments, a mean total thickness of the elastic layersis at least 90% (e.g., from 90 to 99%) of the mean thickness of thematrix.

As exemplified in the Examples section herein, multi-layer matrices asdescribed herein exhibit a considerably degree of water-impermeability.

In some embodiments of any one of the embodiments described herein, thematrix is characterized by a water-permeability of less than 1 ml perhour per cm² upon exposure to an aqueous liquid at a pressure of 40mmHg. In some such embodiments, the water-permeability is less than 0.3ml per hour per cm². In some embodiments, the water-permeability is lessthan 0.1 ml per hour per cm². In some embodiments, thewater-permeability is less than 0.03 ml per hour per cm². In someembodiments, the water-permeability is less than 0.01 ml per hour percm².

In some embodiments of any one of the embodiments described herein, thematrix is characterized by a water-permeability of less than 1 ml perhour per cm² upon exposure to an aqueous liquid at a pressure of 15mmHg. In some such embodiments, the water-permeability is less than 0.3ml per hour per cm². In some embodiments, the water-permeability is lessthan 0.1 ml per hour per cm². In some embodiments, thewater-permeability is less than 0.03 ml per hour per cm². In someembodiments, the water-permeability is less than 0.01 ml per hour percm².

Herein, water-permeability is determined in accordance with ISO 811,according to procedures as described in the Examples section below. Thematrix is placed at the bottom of a column of aqueous liquid (optionallywater, and optionally phosphate buffer saline) having a height whichprovides the indicated pressure, at 37° C. The area of the matrixexposed to the liquid is optionally about 9 cm². The amount of aqueousliquid which passes the matrix during the course of a given period oftime (optionally 30 minutes), when divided by the period of time and thearea exposed to the liquid, determines the water-permeability.

In some embodiments of any one of the embodiments described herein, thecomposition-of-matter further comprising at least one additionalingredient (also referred to herein as “additive”) which imparts anadditional functionality.

In some such embodiments, the additional ingredient(s) is in a form ofat least one additional layer. The additional layer(s) is optionally onat least a portion of at least one surface of the core matrix and/orwithin the core matrix (e.g., between two other layers of the corematrix, as described herein).

Alternatively or additionally, in some embodiments, the additionalingredient(s) is dispersed within the core matrix and/or present on atleast one surface, or a portion thereof, of the matrix.

Except where indicated otherwise, an additional ingredient is consideredherein as part of the matrix when present within the core matrix, butnot when present outside the matrix (e.g., on a surface or a portion ofa surface of the matrix).

Examples of additional functionalities which may be imparted by anadditional ingredient include, without limitation, water-impermeability,which may optionally be provided by an additive in a form of awater-impermeable layer and/or by a hydrophobic additive); inhibition offormation of an adhesion to tissue, which may be optionally be providedby an additive characterized by reduced adhesion to tissue, and/or by anagent which inhibits cell growth; reduction of risk of infection, whichmay optionally be provided by an antimicrobial agent, such as anantibiotic, and/or by a film which inhibits penetration of pathogens;reduction of risk of tissue rejection and/or immune response, which mayoptionally be provided by an agent which modulates an immune system; andadhesion to tissue without suturing, which may optionally be provided byan adhesive (e.g., applied on a surface) and/or an agent and/or surfacewhich promotes cell growth and/or attachment (e.g., growth factors,extracellular matrix proteins, and/or other proteins). Examples oflayers which may be formed from additional ingredients which impart suchfunctionalities include, without limitation, water-impermeable layers,tissue-adhesive layers (i.e., layers characterized by enhanced adherenceto cells, as compared with the core matrix without a tissue-adhesivelayer), cell growth-promoting layers and anti-fouling layers (i.e.,layers characterized by reduced adherence to cells, as compared with thecore matrix without an anti-fouling layer).

Examples of additional ingredients which may be included in thecomposition-of-matter ingredient include, without limitation, adhesivematerials, non-adhesive materials (e.g., materials characterize byparticularly low adherence to tissue and/or other substrate),hydrophobic polymer particles, biological and/or bio-active materials,cellular components (e.g., a cell signaling protein, an extracellularmatrix protein, a cell adhesion protein, a growth factor, protein A, aprotease and a protease substrate), growth factors and therapeuticallyactive agents.

Additional ingredients (e.g., therapeutically active agents) which canbe beneficially incorporated into the composition-of-matter include bothnatural or synthetic polymeric (macro-biomolecules, for example,proteins, enzymes) and non-polymeric (small molecule therapeutics)natural or synthetic agents.

Examples of suitable therapeutically active agents include, withoutlimitation, anti-proliferative agents, cytotoxic factors or cell cycleinhibitors, including CD inhibitors, such as p53, thymidine kinase(“TK”) and other agents useful for interfering with cell proliferation.

Examples of therapeutically active agents that inhibit cellproliferation and/or angiogenesis (antiproliferative drugs) which areparticularly useful in drug-eluting systems destined for anticancertreatment, include paclitaxel, sirolimus (rapamycin),farnesylthiosalicylate (FTS, salirasib), fluoro-FTS, everolimus,zotarolimus, daunorubicin, doxorubicin,N-(5,5-diacetoxypentyl)doxorubicin, anthracycline, mitomycin C,mitomycin A, 9-amino camptothecin, aminopertin, antinomycin, N⁸-acetylspermidine, 1-(2-chloroethyl)-1,2-dimethanesulfonyl hydrazine,bleomycin, tallysomucin, etoposide, camptothecin, irinotecan, topotecan,9-amino camptothecin, paclitaxel, docetaxel, esperamycin,1,8-dihydroxy-bicyclo[7.3.1]trideca-4-ene-2,6-diyne-13-one, anguidine,morpholino-doxorubicin, vincristine, vinblastine and derivativesthereof.

Additional therapeutically active agents which can be beneficiallyincorporated into the composition-of-matter include antibiotic agents.Non-limiting examples of suitable antibiotic agents include gentamicin,ceftazidime, mafenide benzoyl peroxide, octopirox, erythromycin, zinc,silver, tetracyclin, triclosan, azelaic acid and its derivatives,phenoxyethanol and phenoxypropanol, ethyl acetate, clindamycin andmeclocycline; sebostats such as flavinoids; alpha and beta hydroxyacids; polydiallyldimethylammonium chloride and bile salts such asscymnol sulfate and its derivatives, deoxycholate and cholate.

Additional therapeutically active agents which can be beneficiallyincorporated into the composition-of-matter include analgesic agents,anaesthetic agents, pain-killers, pain-reducers and the like (includingNSAIDs, COX-2 inhibitors, K+ channel openers, opiates andmorphinomimetics); and hemostatic agents and antihemorrhagic agents.

According to an aspect of some embodiments of the invention, there isprovided a suturable and/or stapleable matrix capable of self-recovery.

Herein, the term “suturable” refers to an ability to have a needle passthrough the matrix without causing a rupture (e.g., a crack or tear) inthe matrix other than a localized hole similar in area to the needlecross-section.

Herein, the term “stapleable” refers to an ability to have a staple passthrough the matrix without causing a rupture (e.g., a crack or tear) inthe matrix other than a localized hole similar in area to the staplecross-section.

The needle and staple in the above definitions of “suturable” and“stapleable” have a cross-section (optionally, a circular cross-section)of no more than 1 mm². Optionally, the needle is a 21-gauge needle(diameter ˜0.51 mm).

Herein, the term “self-recover” refers to an ability of a material(e.g., material in the matrix) to at least partially close a hole formedin the material (optionally by a 21-gauge needle) by movement of aportion of the material into the space of the hole (e.g., by elasticrebound and/or plastic deformation), such that a hole remaining in thematerial the needle (if any) is less than 50% of an area of across-section of the object which formed the hole (e.g., optionally by a21-gauge needle).

According to an aspect of some embodiments of the invention there isprovided a multi-layer matrix comprising at least one layer of anelastic polymeric material (e.g., according to any one of the respectiveembodiments described herein) and at least one layer of a viscoelasticpolymeric material (e.g., according to any one of the respectiveembodiments described herein), the matrix being characterized by awater-permeability of less than 1 ml per hour per cm² upon exposure toan aqueous liquid at a pressure of 40 mmHg (as defined herein). In somesuch embodiments, the matrix is a suturable matrix capable ofself-recovery (e.g., according to any one of the respective embodimentsdescribed herein). Additionally, some embodiments of any of theembodiments described herein which relate to a matrix exhibit theaforementioned water-permeability.

In some embodiments of any one of the embodiments described herein, amatrix according to an of the aspects described herein exhibits a sutureretention ability characterized in that a minimum mean force applied toa suture in the matrix which is sufficient to cause failure of thematrix is at least 100 grams force, and optionally at least 200 gramsforce.

Suture retention is tested based on the method described in theANSI/AAMI/ISO 7198:1998/2001/(R) 2004 standard, as described in theExamples section below. The matrix is sutured with a single 4/0 suture(e.g., Premilene® 4/0 suture) at a minimum distance of 2 mm from itsfree end, and a tensile test is conducted (e.g., as described herein) inorder to measure the force at failure of the matrix.

The Elastic Layer:

An elastic layer according to any one of the embodiments described inthis section described in this section may be combined with aviscoelastic polymeric material and/or viscoelastic layer according toany one of the respective embodiments described herein.

In some embodiments of any one of the embodiments described herein, theelastic layer is a porous layer.

Herein, the phrase “porous layer” refers to a layer which comprisesvoids (e.g., in addition to polymeric material described herein), forexample, the space between the polymeric material is not filled in by anadditional substance. However, porous layers may optionally comprise anadditional substance in the spaces between the polymeric material,provided that at least a portion of the volume of the voids is notfilled in by the additional substance.

Porous layers may be, for example, in a form of fibers (e.g., woven ornon-woven fibers, a foam and/or a sponge. Many suitable techniques willbe known to the skilled practitioner for preparing a polymeric materialin porous form, including, without limitation, various techniques forspinning fibers, use of a gas to form a foam, and drying (e.g.,lyophilizing) a suspension of polymeric material.

In some embodiments of any one of the embodiments described hereinrelating to one or more porous layers (e.g., porous elastic layers), theporous layers are characterized by a porosity of at least 50% (e.g.,from 50 to 99%). In some such embodiments, the porous layers arecharacterized by a porosity of at least 60% (e.g., from 60 to 99%). Insome such embodiments, the porous layers are characterized by a porosityof at least 70% (e.g., from 70 to 99%). In some such embodiments, theporous layers are characterized by a porosity of at least 80% (e.g.,from 80 to 99%). In some such embodiments, the porous layers arecharacterized by a porosity of at least 90% (e.g., from 90 to 99%). Insome such embodiments, the porous layers are characterized by a porosityof about 90%.

As shown in the Examples section herein, the present inventors havesurprisingly uncovered that even a highly porous elastic layer reducesmatrix water-permeability considerably.

Herein, the term “porosity” refers to a percentage of the volume of asubstance (e.g., an elastic polymeric material described herein) whichconsists of voids.

In some embodiments of any one of the embodiments described herein, oneor more elastic layers (e.g., porous elastic layers, according to any ofthe respective embodiments described herein) are independently made ofpolymeric fibers.

Without being bound by any particular theory, it is believed that afibrous structure of an elastic layer made of polymeric fibersadvantageously allows a needle to pass through the layer by pushingfibers aside without any considerable amount of permanent deformation ormechanical disruption of the layers, and that the elasticity of thefibers causes the layers to rebound, thereby closing suture holes andholding tightly to sutures.

In some embodiments of any one of the embodiments described herein, thefibers are polymeric fibers.

The fibers which form the elastic layers may be woven or non-woven. Insome embodiments of any one of the embodiments described herein, thefibers are non-woven.

In some embodiments of any one of the embodiments described herein, thefibers in the elastic layer(s) are electrospun.

Without being bound by any particular theory, it is believed thatelectrospun fibers, and structurally similar fibers, are particularlysuitable for forming elastic layers such as described herein. Inparticular, layers of electrospun fibers can be prepared from a widevariety of materials, and allow control over pore size, fiber size,fiber alignment, hydrophobicity, elasticity and mechanical strength.

In some embodiments of any one of the embodiments described hereinrelating to polymeric fibers, at least 20 weight percents (by dryweight) of the polymeric fiber consists of one or more polymers. In someembodiments, at least 30 weight percents (by dry weight) of thepolymeric fiber consists of one or more polymers. In some embodiments,at least 40 weight percents (by dry weight) of the polymeric fiberconsists of one or more polymers. In some embodiments, at least 50weight percents (by dry weight) of the polymeric fiber consists of oneor more polymers. In some embodiments, at least 60 weight percents (bydry weight) of the polymeric fiber consists of one or more polymers. Insome embodiments, at least 70 weight percents (by dry weight) of thepolymeric fiber consists of one or more polymers. In some embodiments,at least 80 weight percents (by dry weight) of the polymeric fiberconsists of one or more polymers. In some embodiments, at least 90weight percents (by dry weight) of the polymeric fiber consists of oneor more polymers. In some embodiments, the polymeric fiber consistsessentially of one or more polymers.

In some embodiments of any one of the embodiments described herein, thefibers (e.g., polymeric fibers according to any of the respectiveembodiments described herein) in at least one of the porous layers offibers (according to any one of the respective embodiments describedherein) are characterized by a mean diameter in a range of from 0.001 to30 μm. In some such embodiments, the mean diameter is in a range of from0.003 to 30 μm. In some such embodiments, the mean diameter is in arange of from 0.01 to 30 μm. In some such embodiments, the mean diameteris in a range of from 0.03 to 30 μm. In some such embodiments, the meandiameter is in a range of from 0.1 to 30 μm. In some such embodiments,the mean diameter is in a range of from 0.3 to 30 μm. In some suchembodiments, the mean diameter is in a range of from 1 to 10 μm. In somesuch embodiments, the mean diameter is in a range of from 1 to 4 μm. Insome such embodiments, the mean diameter is about 3 μm.

In some embodiments of any one of the embodiments described herein, thefibers (e.g., polymeric fibers according to any of the respectiveembodiments described herein) in each of the porous layers of fibers(according to any one of the respective embodiments described herein)are characterized by a mean diameter in a range of from 0.001 to 30 μm.In some such embodiments, the mean diameter is in a range of from 0.003to 30 μm. In some such embodiments, the mean diameter is in a range offrom 0.01 to 30 μm. In some such embodiments, the mean diameter is in arange of from 0.03 to 30 μm. In some such embodiments, the mean diameteris in a range of from 0.1 to 30 μm. In some such embodiments, the meandiameter is in a range of from 0.3 to 30 μm. In some such embodiments,the mean diameter is in a range of from 1 to 10 μm. In some suchembodiments, the mean diameter is in a range of from 1 to 4 μm. In somesuch embodiments, the mean diameter is about 3 μm.

In some embodiments of any one of the embodiments described herein, thefibers in at least one of the porous layers of fibers (according to anyone of the respective embodiments described herein) are characterized bya mean diameter in a range of from 0.001 to 10 μm. In some suchembodiments, the mean diameter is in a range of from 0.3 to 3 μm. Insome such embodiments, the mean diameter is in a range of from 0.3 to 1μm.

In some embodiments of any one of the embodiments described herein, thefibers in each of the porous layers of fibers (according to any one ofthe respective embodiments described herein) are characterized by a meandiameter in a range of from 0.3 to 10 μm. In some such embodiments, themean diameter is in a range of from 0.3 to 3 μm. In some suchembodiments, the mean diameter is in a range of from 0.3 to 1 μm.

In some embodiments of any one of the embodiments described herein, thefibers in at least one of the porous layers of fibers (according to anyone of the respective embodiments described herein) are characterized bya mean diameter in a range of from 1 to 30 μm. In some such embodiments,the mean diameter is in a range of from 3 to 30 μm. In some suchembodiments, the mean diameter is in a range of from 10 to 30 μm.

In some embodiments of any one of the embodiments described herein, thefibers in each of the porous layers of fibers (according to any one ofthe respective embodiments described herein) are characterized by a meandiameter in a range of from 1 to 30 μm. In some such embodiments, themean diameter is in a range of from 3 to 30 μm. In some suchembodiments, the mean diameter is in a range of from 10 to 30 μm.

In some embodiments of any one of the embodiments described herein, atleast one of the elastic layers (according to any one of the respectiveembodiments described herein) is characterized by a mean thickness in arange of from 10 to 500 μm. In some such embodiments, the mean thicknessis in a range of from 25 to 350 μm. In some such embodiments, the meanthickness is in a range of from 50 to 250 μm.

In some embodiments of any one of the embodiments described herein, eachof the elastic layers (according to any one of the respectiveembodiments described herein) is characterized by a mean thickness in arange of from 10 to 500 μm. In some such embodiments, the mean thicknessis in a range of from 25 to 350 μm. In some such embodiments, the meanthickness is in a range of from 50 to 250 μm.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer according to any of the respective embodimentsdescribed herein is characterized by at least one of the following 3properties:

a) an elastic modulus (Young's modulus) in a range of from 1 kPa to 1GPa;

b) an elongation at failure of at least 100% (e.g., in a range of from100% to 1000%); and

c) a glass transition temperature and/or melting point of said elasticpolymeric material which is at a temperature above 40° C.

Herein throughout, the phrase “elastic modulus” refers to Young'smodulus, as determined by response of a material to application oftensile stress (e.g., according to procedures described in the Examplessection herein).

Tensile properties described herein (e.g., elastic modulus, elongationat failure, recovery and ultimate tensile strength) are determined inaccordance with ASTM international standard D882-12 for testing tensileproperties of thin plastic sheeting. Except where indicated otherwise,the tensile properties are determined after the layers are immersed inaqueous liquid (e.g., water, phosphate buffer saline), and at atemperature of 37° C. (e.g., according to procedures described in theExamples section herein). Tensile testing characterizes an amount oftensile stress applied to the tested material as a function of tensilestrain (increase in length due to tensile stress, as a percentage of theoriginal length) of the material.

The ultimate tensile strength is determined as the maximal stress whichcan be applied to the tested material, such that any further strain isobtained with reduced stress (a phenomenon known as “necking” or isunobtainable because the tensile stress results in rupture (e.g.,tearing, cracking) of the material.

The elongation at failure is determined as the maximal strain(elongation) which can occur (upon application of tensile stress equalto the ultimate tensile strength) before failure of the tested materialoccurs (e.g., as rupture or necking).

The elastic modulus is determined as the gradient of stress as afunction of strain over ranges of stress and strain wherein stress is alinear function of strain (e.g., from a stress and strain of zero, tothe elastic proportionality limit, and optionally from zero strain to astrain which is no more than 50% of the elongation at failure).

Recovery is determined by releasing the tensile stress after subjectingthe tested material as the ratio of the decrease in length to a priorstrain after a material (e.g., elastic layer) is subjected to a priorstrain which is almost equal to the elongation at failure (optionallyabout 90% of the elongation at failure, optionally about 95% of theelongation at failure, optionally about 98% of the elongation atfailure, optionally about 99% of the elongation at failure, wherein theelongation at failure can be determined using an equivalent sample).Thus, for example, a material extended to an elongation at failure whichis 200%, and which upon release of tensile stress returns to a statecharacterized by a strain of 20% relative to the original length, wouldbe characterized as having a recovery of 90% (i.e., 200%-20% divided by200%).

In some embodiments of any one of the embodiments described herein, eachof the elastic layers in a matrix according to any of the respectiveembodiments described herein is characterized by at least one of theabovementioned 3 properties.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer (according to any of the respective embodimentsdescribed herein) is characterized by at least two of the abovementioned3 properties. In some such embodiments, each of the elastic layers in amatrix (according to any of the respective embodiments described herein)is characterized by at least two of the abovementioned 3 properties.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer (according to any of the respective embodimentsdescribed herein) is characterized by each of the abovementioned 3properties. In some such embodiments, each of the elastic layers in amatrix (according to any of the respective embodiments described herein)is characterized by each of the abovementioned 3 properties.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by a recovery of at least 75%(e.g., from 75 to 99.9%). In some such embodiments, the recovery is atleast 80% (e.g., from 80 to 99.9%). In some such embodiments, therecovery is at least 85% (e.g., from 85 to 99.9%). In some suchembodiments, the recovery is at least 90% (e.g., from 90 to 99.9%). Insome such embodiments, the recovery is at least 95% (e.g., from 95 to99.9%).

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an elastic modulus (Young'smodulus) in a range of from 1 kPa to 1 GPa. In some such embodiments,the elastic modulus is in a range of from 3 kPa to 500 MPa. In some suchembodiments, the elastic modulus is in a range of from 10 kPa to 200MPa. In some such embodiments, the elastic modulus is in a range of from20 kPa to 100 MPa. In some such embodiments, the elastic modulus is in arange of from 50 kPa to 50 MPa. In some such embodiments, the elasticmodulus is in a range of from 50 kPa to 20 MPa. In some suchembodiments, the elastic modulus is in a range of from 50 kPa to 10 MPa.In some such embodiments, the elastic modulus is in a range of from 100kPa to 3 MPa. In some such embodiments, each of the elastic layers in amatrix (according to any of the respective embodiments described herein)is characterized by an elastic modulus in a range according to any ofthe aforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an elastic modulus (Young'smodulus) in a range of from 1 kPa to 300 MPa. In some such embodiments,the elastic modulus is in a range of from 1 kPa to 100 MPa. In some suchembodiments, the elastic modulus is in a range of from 1 kPa to 30 MPa.In some such embodiments, the elastic modulus is in a range of from 1kPa to 10 MPa. In some such embodiments, the elastic modulus is in arange of from 1 kPa to 3 MPa. In some such embodiments, the elasticmodulus is in a range of from 1 kPa to 1 MPa. In some such embodiments,the elastic modulus is in a range of from 3 kPa to 1 MPa. In some suchembodiments, the elastic modulus is in a range of from 10 kPa to 1 MPa.In some such embodiments, the elastic modulus is in a range of from 30kPa to 1 MPa. In some such embodiments, each of the elastic layers in amatrix (according to any of the respective embodiments described herein)is characterized by an elastic modulus in a range according to any ofthe aforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an elastic modulus (Young'smodulus) in a range of from 3 kPa to 1 GPa. In some such embodiments,the elastic modulus is in a range of from 10 kPa to 1 GPa. In some suchembodiments, the elastic modulus is in a range of from 30 kPa to 1 GPa.In some such embodiments, the elastic modulus is in a range of from 100kPa to 1 GPa. In some such embodiments, the elastic modulus is in arange of from 300 kPa to 1 GPa. In some such embodiments, the elasticmodulus is in a range of from 300 kPa to 300 MPa. In some suchembodiments, the elastic modulus is in a range of from 300 kPa to 100MPa. In some such embodiments, the elastic modulus is in a range of from300 kPa to 30 MPa. In some such embodiments, the elastic modulus is in arange of from 300 kPa to 10 MPa. In some such embodiments, each of theelastic layers in a core matrix (according to any of the respectiveembodiments described herein) is characterized by an elastic modulus ina range according to any of the aforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an elongation at failure ofat least 10%. In some such embodiments, the elongation at failure is ina range of from 10% to 1000%. In some such embodiments, the elongationat failure is at least 20%. In some such embodiments, the elongation atfailure is in a range of from 20% to 1000%. In some such embodiments,the elongation at failure is at least 50%. In some such embodiments, theelongation at failure is in a range of from 50% to 1000%. In some suchembodiments, the elongation at failure is at least 100%. In some suchembodiments, the elongation at failure is in a range of from 100% to1000%. In some such embodiments, the elongation at failure is at least200%. In some such embodiments, the elongation at failure is in a rangeof from 200% to 1000%. In some such embodiments, the elongation atfailure is in a range of from 200% to 600%. In some such embodiments,each of the elastic layers in a core matrix (according to any of therespective embodiments described herein) is characterized by anelongation at failure in a range according to any of the aforementionedembodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an elongation at failure ofat least 10% (according to any of the respective embodiments describedherein) and an elastic modulus in a range of from 1 kPa to 1 GPa(according to any of the respective embodiments described herein). Insome such embodiments, each of the elastic layers in a matrix (accordingto any of the respective embodiments described herein) is characterizedby an elongation at failure and elastic modulus in a range according toany of the aforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an elongation at failure ofat least 100% (according to any of the respective embodiments describedherein) and a recovery of at least 75% (according to any of therespective embodiments described herein). In some such embodiments, eachof the elastic layers in a core matrix (according to any of therespective embodiments described herein) is characterized by anelongation at failure and recovery in a range according to any of theaforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an elastic modulus in arange of from 1 kPa to 1 GPa (according to any of the respectiveembodiments described herein) and a recovery of at least 75% (accordingto any of the respective embodiments described herein). In some suchembodiments, each of the elastic layers in a matrix (according to any ofthe respective embodiments described herein) is characterized by anelastic modulus and recovery in a range according to any of theaforementioned embodiments.

In some such embodiments, the elongation at failure is at least 100%. Insome such embodiments, the elongation at failure is in a range of from100% to 1000%. In some such embodiments, the elongation at failure is atleast 200%. In some such embodiments, the elongation at failure is in arange of from 200% to 1000%. In some such embodiments, the elongation atfailure is in a range of from 200% to 600%. In some such embodiments,each of the elastic layers in a matrix (according to any of therespective embodiments described herein) is characterized by anelongation at failure in a range according to any of the aforementionedembodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an ultimate tensile strengthof at least 0.05 MPa. In some embodiments of any one of the embodimentsdescribed herein, at least one elastic layer is characterized by anultimate tensile strength of at least 1 MPa. In some embodiments of anyone of the embodiments described herein, at least one elastic layer ischaracterized by an ultimate tensile strength of at least 2 MPa. In someembodiments of any one of the embodiments described herein, at least oneelastic layer is characterized by an ultimate tensile strength of atleast 4 MPa. In some such embodiments, each of the elastic layers in amatrix (according to any of the respective embodiments described herein)is characterized by an ultimate tensile strength according to any of theaforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an ultimate tensile strengthof at least 0.05 MPa, and an elongation at failure of at least 100%. Insome such embodiments, the elongation at failure is in a range of from100% to 1000%. In some such embodiments, the elongation at failure is atleast 200%. In some such embodiments, the elongation at failure is in arange of from 200% to 1000%. In some such embodiments, the elongation atfailure is in a range of from 200% to 600%. In some such embodiments,each of the elastic layers in a matrix (according to any of therespective embodiments described herein) is characterized by an ultimatetensile strength and elongation at failure in a range according to anyof the aforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an ultimate tensile strengthof at least 1 MPa, and an elongation at failure of at least 100%. Insome such embodiments, the elongation at failure is in a range of from100% to 1000%. In some such embodiments, the elongation at failure is atleast 200%. In some such embodiments, the elongation at failure is in arange of from 200% to 1000%. In some such embodiments, the elongation atfailure is in a range of from 200% to 600%. In some such embodiments,each of the elastic layers in a core matrix (according to any of therespective embodiments described herein) is characterized by an ultimatetensile strength and elongation at failure in a range according to anyof the aforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an ultimate tensile strengthof at least 2 MPa, and an elongation at failure of at least 100%. Insome such embodiments, the elongation at failure is in a range of from100% to 1000%. In some such embodiments, the elongation at failure is atleast 200%. In some such embodiments, the elongation at failure is in arange of from 200% to 1000%. In some such embodiments, the elongation atfailure is in a range of from 200% to 600%. In some such embodiments,each of the elastic layers in a core matrix (according to any of therespective embodiments described herein) is characterized by an ultimatetensile strength and elongation at failure in a range according to anyof the aforementioned embodiments.

In some embodiments of any one of the embodiments described herein, atleast one elastic layer is characterized by an ultimate tensile strengthof at least 4 MPa, and an elongation at failure of at least 100%. Insome such embodiments, the elongation at failure is in a range of from100% to 1000%. In some such embodiments, the elongation at failure is atleast 200%. In some such embodiments, the elongation at failure is in arange of from 200% to 1000%. In some such embodiments, the elongation atfailure is in a range of from 200% to 600%. In some such embodiments,each of the elastic layers in a matrix (according to any of therespective embodiments described herein) is characterized by an ultimatetensile strength and elongation at failure in a range according to anyof the aforementioned embodiments.

In most embodiments, the mechanical properties of the matrix as a wholewill be strongly dependent on the mechanical properties of the elasticlayer.

In some embodiments of any one of the embodiments described herein, thematrix (according to any of the respective embodiments described herein)is characterized by an elastic modulus which is within a range of 50% to200% of an elastic modulus of at least one of the elastic layers, andoptionally within a range of 50% to 200% of an elastic modulus of eachof the elastic layers in the matrix. In some embodiments, the matrixelastic modulus is within a range of 80% to 120% of an elastic modulusof at least one of the elastic layers. In some embodiments, the matrixelastic modulus is within a range of 80% to 120% of an elastic modulusof each of the elastic layers in the matrix. In some embodiments of anyof the aforementioned embodiments, the matrix contains one viscoelasticlayer interposed between two elastic layers (according to any of therespective embodiments described herein), and the matrix elastic modulusis within a range of 50% to 200% (and optionally 80% to 120%) of anelastic modulus of at least one (optionally both) of the aforementionedtwo elastic layers.

The Viscoelastic Layer:

A viscoelastic polymeric material and/or viscoelastic layer according toany one of the embodiments described in this section described in thissection may be combined with an elastic layer according to any one ofthe respective embodiments described herein.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a glasstransition temperature and/or melting point at a temperature below 40°C. In some embodiments, the polymer is characterized by a glasstransition temperature and/or melting point at a temperature below 35°C. In some embodiments, the polymer is characterized by a glasstransition temperature and/or melting point at a temperature below 30°C. In some embodiments, the polymer is characterized by a glasstransition temperature and/or melting point at a temperature below 25°C. In some embodiments, the polymer is characterized by a glasstransition temperature and/or melting point at a temperature below 20°C. In some embodiments, the polymer is characterized by a glasstransition temperature and/or melting point at a temperature below 15°C. In some embodiments, the polymer is characterized by a glasstransition temperature and/or melting point at a temperature below 10°C. In some embodiments, the polymer is characterized by a glasstransition temperature and/or melting point at a temperature below 5° C.In some embodiments, the polymer is characterized by a glass transitiontemperature and/or melting point at a temperature below 0° C.

Herein, a glass transition temperature is preferably determinedaccording to differential scanning calorimetry, using proceduresaccepted in the art for such a purpose, using cooling and heating ratesof 10° C. per minute. The glass transition typically appears as anintersection between two linear regions in a plot of heat capacity as afunction of temperature.

In some embodiments of any one of the embodiments described herein, theviscoelastic polymeric material comprises a polymer characterized by aglass transition temperature and/or melting point at a temperature whichis at least 5° C. lower than an ambient temperature of thecomposition-of-matter. In some such embodiments, the glass transitiontemperature and/or melting point is at a temperature which is at least10° C. lower than an ambient temperature of the composition-of-matter.In some such embodiments, glass transition temperature and/or meltingpoint is at a temperature which is at least 20° C. lower than an ambienttemperature of the composition-of-matter.

In some embodiments of any one of the embodiments described herein, theviscoelastic polymeric material comprises a polymer characterized by aglass transition temperature at a temperature which is at least 5° C.lower than an ambient temperature of the composition-of-matter. In somesuch embodiments, the glass transition temperature is at a temperaturewhich is at least 10° C. lower than an ambient temperature of thecomposition-of-matter. In some such embodiments, glass transitiontemperature is at a temperature which is at least 20° C. lower than anambient temperature of the composition-of-matter.

Herein, the phrase “ambient temperature of the composition-of-matter”generally refers to 20° C., except in the context ofarticles-of-manufacture comprising the composition-of-matter, in whichcase the phrase “ambient temperature of the composition-of-matter”refers to a temperature at which the article-of-manufacture is typicallyused, for example, body temperature in the context of anarticle-of-manufacture (e.g., medical device) for use inside a body(i.e., 37° C. for articles-of-manufacture for use inside a human body).

Without being bound by any particular theory, it is believed that for arelatively amorphous (i.e., relatively low-crystallinity) polymer, theglass transition temperature has a relatively strong effect on therheological and mechanical properties of the polymer, whereas a meltingpoint may be less significant and even absent. Similarly, is believedthat for a relatively crystalline (i.e., relatively high-crystallinity)polymer, the melting point has a relatively strong effect on therheological and mechanical properties of the polymer, whereas a glasstransition temperature may be less significant and even absent.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof at least 20%, and a melting point at a temperature below 40° C. Insome such embodiments, the polymer is characterized by a melting pointat a temperature below 35° C. In some such embodiments, the polymer ischaracterized by a melting point at a temperature below 30° C. In somesuch embodiments, the polymer is characterized by a melting point at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 20° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 15° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 10° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof at least 30%, and a melting point at a temperature below 40° C. Insome such embodiments, the polymer is characterized by a melting pointat a temperature below 35° C. In some such embodiments, the polymer ischaracterized by a melting point at a temperature below 30° C. In somesuch embodiments, the polymer is characterized by a melting point at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 20° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 15° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 10° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof at least 40%, and a melting point at a temperature below 40° C. Insome such embodiments, the polymer is characterized by a melting pointat a temperature below 35° C. In some such embodiments, the polymer ischaracterized by a melting point at a temperature below 30° C. In somesuch embodiments, the polymer is characterized by a melting point at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 20° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 15° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 10° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof at least 50%, and a melting point at a temperature below 40° C. Insome such embodiments, the polymer is characterized by a melting pointat a temperature below 35° C. In some such embodiments, the polymer ischaracterized by a melting point at a temperature below 30° C. In somesuch embodiments, the polymer is characterized by a melting point at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 20° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 15° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 10° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof at least 60%, and a melting point at a temperature below 40° C. Insome such embodiments, the polymer is characterized by a melting pointat a temperature below 35° C. In some such embodiments, the polymer ischaracterized by a melting point at a temperature below 30° C. In somesuch embodiments, the polymer is characterized by a melting point at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 20° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 15° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 10° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof at least 70%, and a melting point at a temperature below 40° C. Insome such embodiments, the polymer is characterized by a melting pointat a temperature below 35° C. In some such embodiments, the polymer ischaracterized by a melting point at a temperature below 30° C. In somesuch embodiments, the polymer is characterized by a melting point at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 20° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 15° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 10° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof at least 80%, and a melting point at a temperature below 40° C. Insome such embodiments, the polymer is characterized by a melting pointat a temperature below 35° C. In some such embodiments, the polymer ischaracterized by a melting point at a temperature below 30° C. In somesuch embodiments, the polymer is characterized by a melting point at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 20° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 15° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 10° C. In someembodiments, the polymer is characterized by a melting point at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a melting point at a temperature below 0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 80%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 70%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 60%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 50%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 40%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 30%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 20%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described hereinrelating to a viscoelastic polymeric material, the viscoelasticpolymeric material comprises a polymer characterized by a crystallinityof less than 10%, and a glass transition temperature at a temperaturebelow 40° C. In some such embodiments, the polymer is characterized by aglass transition temperature at a temperature below 35° C. In some suchembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 30° C. In some such embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 25° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below20° C. In some embodiments, the polymer is characterized by a glasstransition temperature at a temperature below 15° C. In someembodiments, the polymer is characterized by a glass transitiontemperature at a temperature below 10° C. In some embodiments, thepolymer is characterized by a glass transition temperature at atemperature below 5° C. In some embodiments, the polymer ischaracterized by a glass transition temperature at a temperature below0° C.

In some embodiments of any one of the embodiments described herein, theviscoelastic polymeric material comprises (and optionally consistsessentially of) one or more polymers which are biocompatible and/orbiodegradable (as defined herein).

Poly(lactic acid-co-ε-caprolactone) (optionally poly(DL-lacticacid-co-ε-caprolactone, either alone or in combination withpoly(L-lactic acid-co-ε-caprolactone) and/or poly(D-lacticacid-co-ε-caprolactone)) is an exemplary biocompatible and biodegradablepolymer, which may be included in a viscoelastic polymeric materialaccording to any of the respective embodiments described herein. In somesuch embodiments, the viscoelastic polymeric material consistsessentially of poly(lactic acid-co-ε-caprolactone).

In some embodiments of any one of the embodiments described herein, theviscoelastic polymeric material comprises (and optionally consistsessentially of) any one or more of the polymers and/or copolymersdescribed herein for use in an elastic layer.

The skilled practitioner will be readily capable of selectingconcentrations of polymers, molecular weights of polymers and/or molarratios of monomers (e.g., lactic acid and ε-caprolactone) in copolymerswhich may provide elastic or viscoelastic properties according to any ofthe respective embodiments described herein relating to elastic and/orviscoelastic polymeric materials.

In some embodiments of any one of the embodiments described herein, theviscoelastic polymeric material comprises (and optionally consistsessentially of) one or more hydrophobic polymers.

Without being bound by any particular theory, it is believed that ahydrophobic polymer may considerably reduce water-permeability of thematrix, even in embodiments in which the viscoelastic polymeric layer isnot in a form of a continuous film. For example, pores in a poroushydrophobic viscoelastic polymeric layer may be too small to allowpassage of water, as contact between the water and hydrophobic polymeris energetically unfavorable.

Herein, a “hydrophobic polymer” is a polymer characterized in that inwater at a pH of 7.0, the polymer (in bulk) has a solubility of lessthan 1 gram per liter, and does not absorb more than 20 weight percentsof water (weight of absorbed water relative to weight of polymer). Insome embodiments, the hydrophobic polymer is characterized in that itdoes not absorb more than 10 weight percents of water at pH 7.0. In someembodiments, the hydrophobic polymeric substance is characterized inthat it does not absorb more than 5 weight percents of water at pH 7.0.In some embodiments, the hydrophobic polymeric substance ischaracterized in that it does not absorb more than 2 weight percents ofwater at pH 7.0. In some embodiments, the hydrophobic polymericsubstance is characterized in that it does not absorb more than 1 weightpercents of water at pH 7.0.

The skilled practitioner will be readily capable of selecting polymers(e.g., polymers described herein), molecular weights of polymers and/ormolar ratios of monomers (e.g., lactic acid and ε-caprolactone) incopolymers which result in a hydrophobic polymer as defined herein.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any one of the respective embodimentsdescribed herein) is characterized by a mean thickness in a range offrom 1 to 300 μm. In some such embodiments, the mean thickness is in arange of from 2 to 250 μm. In some such embodiments, the mean thicknessis in a range of from 3 to 200 μm. In some such embodiments, the meanthickness is in a range of from 5 to 150 μm. In some such embodiments,the mean thickness is in a range of from 10 to 100 μm. In some suchembodiments, the mean thickness is in a range of from 15 to 60 μm.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any one of the respective embodimentsdescribed herein) is characterized by a mean thickness in a range offrom 1 to 200 μm. In some such embodiments, the mean thickness is in arange of from 1 to 100 μm. In some such embodiments, the mean thicknessis in a range of from 1 to 60 μm. In some such embodiments, the meanthickness is in a range of from 1 to 30 μm.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any one of the respective embodimentsdescribed herein) is characterized by a mean thickness in a range offrom 2 to 300 μm. In some such embodiments, the mean thickness is in arange of from 5 to 300 μm. In some such embodiments, the mean thicknessis in a range of from 10 to 300 μm. In some such embodiments, the meanthickness is in a range of from 20 to 300 μm. In some such embodiments,the mean thickness is in a range of from 40 to 300 μm.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is a non-porous, continuous film or is characterizedby a limited porosity.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer is characterized by a porosity which is lower than aporosity of each of the adjacent elastic layers (according to any of therespective embodiments described herein). In some such embodiments, theviscoelastic layer is characterized by a porosity which is less than 75%of a porosity of each of the adjacent elastic layers (according to anyof the respective embodiments described herein). In some suchembodiments, the viscoelastic layer is characterized by a porosity whichis less than 50% of a porosity of each of the adjacent elastic layers(according to any of the respective embodiments described herein). Insome such embodiments, the viscoelastic layer is characterized by aporosity which is less than 25% of a porosity of each of the adjacentelastic layers (according to any of the respective embodiments describedherein). In some such embodiments, the viscoelastic layer ischaracterized by a porosity which is less than 15% of a porosity of eachof the adjacent elastic layers (according to any of the respectiveembodiments described herein). In some such embodiments, theviscoelastic layer is characterized by a porosity which is less than 10%of a porosity of each of the adjacent elastic layers (according to anyof the respective embodiments described herein). In some suchembodiments, the viscoelastic layer is characterized by a porosity whichis less than 5% of a porosity of each of the adjacent elastic layers(according to any of the respective embodiments described herein). Insome embodiments of any one of the aforementioned embodiments relatingto porosity of the viscoelastic layer(s), the elastic layers arecharacterized by a porosity of at least 50% (e.g., from 50 to 99%),according to any of the respective embodiments described herein.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer is characterized by a porosity in a range of from 0to 50%. In some such embodiments, the porosity is from 0 to 40%. In somesuch embodiments, the porosity is from 0 to 30%. In some suchembodiments, the porosity is from 0 to 20%. In some such embodiments,the porosity is from 0 to 10%. In some such embodiments, a porosity ofeach of the adjacent elastic layers is higher than the porosity of theviscoelastic layer (e.g., more than 50%).

Without being bound by any particular theory, it is believed that aviscoelastic layer which is non-porous or characterized by limitedporosity (e.g., up to 50%) reduces a permeability of the core matrix towater as well as other liquids, thereby enhancing the ability of thecomposition-of-matter to serve, for example, as a sealant against fluidleakage. It is further believed that such a layer, for example, a layerwhich does not have any fibrous structure, can readily undergodeformation in response to stress by viscous flow, and that suchdeformation can result in closure of holes formed in the viscoelasticlayer.

In some embodiments of any one of the embodiments described herein, theviscoelastic layer is characterized by a porosity (e.g., up to 50%)which is lower than a porosity of the elastic layers (according to anyof the respective embodiments described herein, optionally embodimentswherein a porosity of the elastic layers is at least 50%, at least 60%,at least 70%, at least 80% and/or at least 90%). In some suchembodiments, the viscoelastic layer porosity is no more than half of theelastic layer porosity.

Without being bound by any particular theory, it is believed that theviscoelastic layer acts as a barrier (e.g., to water-permeation), whichmay be more impermeable than elastic layers which are more porous thanthe viscoelastic layer (e.g., porous elastic layers made of fibers),thereby significantly reducing permeability of matrices comprising suchelastic layers.

A continuous film may optionally be prepared, for example, by filmcasting (e.g., as exemplified herein).

A limited porosity may optionally be prepared, for example, by formingfibers of the viscoelastic polymeric material, for example, byelectrospinning (e.g., as exemplified herein), wherein the fiberspartially merge as a result of viscous flow (which is optionallyenhanced by heat treatment and/or pressure), thereby resulting insmaller pores and lower porosity.

In some embodiments of any one of the embodiments described herein, theviscoelastic layer has a fibrous structure. In some such embodiments,the layer comprises fibers which provide mechanical strength, as well asviscoelastic polymeric material in the spaces interposed between thefibers. In some such embodiments, the fibers are more elastic and lessfluid than the viscoelastic polymeric material in the spaces interposedbetween the fibers. For example, in some embodiments, a relatively fluidfraction of the viscoelastic polymeric material exits the fibers byviscous flow, whereas the fraction of the viscoelastic polymericmaterial remaining in the fibers is more solid and/or elastic in nature.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by at least one of the following 4properties

a) a shear storage modulus (G′) in a range of from 0.01 to 10 MPa, at atemperature of 10° C. and frequency of 0.1 Hz;

b) a shear loss modulus (G″) in a range of from 0.0001 to 2 MPa, at atemperature of 10° C. and frequency of 0.1 Hz;

c) a glass transition temperature and/or melting point of theviscoelastic polymeric material which is at a temperature below 40° C.;and

d) a loss tangent (G″/G′) at a temperature of 10° C. and frequency of0.1 Hz which is in a range of from 0.01 to 4.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by at least two of the abovementioned4 properties.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by at least 3 of the abovementioned 4properties.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by each of the abovementioned 4properties.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear storage modulus (G′) in arange of from 0.01 to 10 MPa, at a temperature of 10° C. and frequencyof 0.1 Hz. In some such embodiments, the shear storage modulus is in arange of from 0.05 to 10 MPa. In some such embodiments, the shearstorage modulus is in a range of from 0.1 to 5 MPa. In some suchembodiments, the shear storage modulus is in a range of from 0.2 to 2.5MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear storage modulus (G′) in arange of from 0.01 to 1 MPa, at a temperature of 10° C. and frequency of0.1 Hz. In some such embodiments, the shear storage modulus is in arange of from 0.05 to 1 MPa. In some such embodiments, the shear storagemodulus is in a range of from 0.1 to 1 MPa. In some such embodiments,the shear storage modulus is in a range of from 0.2 to 1 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear storage modulus (G′) in arange of from 0.5 to 10 MPa, at a temperature of 10° C. and frequency of0.1 Hz. In some such embodiments, the shear storage modulus is in arange of from 1 to 10 MPa. In some such embodiments, the shear storagemodulus is in a range of from 2 to 10 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear loss modulus (G″) in arange of from 0.0001 to 2 MPa, at a temperature of 10° C. and frequencyof 0.1 Hz. In some such embodiments, the shear loss modulus is in arange of from 0.0003 to 0.3 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.001 to 0.1 MPa. In some suchembodiments, the shear loss modulus is in a range of from 0.003 to 0.03MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear loss modulus (G″) in arange of from 0.0001 to 0.3 MPa, at a temperature of 10° C. andfrequency of 0.1 Hz. In some such embodiments, the shear loss modulus isin a range of from 0.0001 to 0.1 MPa. In some such embodiments, theshear loss modulus is in a range of from 0.0001 to 0.03 MPa. In somesuch embodiments, the shear loss modulus is in a range of from 0.0001 to0.01 MPa. In some such embodiments, the shear loss modulus is in a rangeof from 0.0001 to 0.003 MPa. In some such embodiments, the shear lossmodulus is in a range of from 0.0001 to 0.001 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear loss modulus (G″) in arange of from 0.0003 to 2 MPa, at a temperature of 10° C. and frequencyof 0.1 Hz. In some such embodiments, the shear loss modulus is in arange of from 0.001 to 1 MPa. In some such embodiments, the shear lossmodulus is in a range of from 0.003 to 1 MPa. In some such embodiments,the shear loss modulus is in a range of from 0.01 to 1 MPa. In some suchembodiments, the shear loss modulus is in a range of from 0.03 to 1 MPa.In some such embodiments, the shear loss modulus is in a range of from0.1 to 1 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′, e.g.,wherein values of G″ and G′ are each individually in accordance with anyof the respective embodiments described herein) in a range of from 0.01to 1, at a temperature of 10° C. and frequency of 0.1 Hz. In some suchembodiments, the loss tangent is in a range of from 0.02 to 0.8. In somesuch embodiments, the loss tangent is in a range of from 0.05 to 0.7. Insome such embodiments, the loss tangent is in a range of from 0.1 to0.6. In some such embodiments, the loss tangent is in a range of from0.175 to 0.5.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′, e.g.,wherein values of G″ and G′ are each individually in accordance with anyof the respective embodiments described herein) in a range of from 0.01to 0.5, at a temperature of 10° C. and frequency of 0.1 Hz. In some suchembodiments, the loss tangent is in a range of from 0.01 to 0.3. In somesuch embodiments, the loss tangent is in a range of from 0.01 to 0.2. Insome such embodiments, the loss tangent is in a range of from 0.01 to0.1.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′, e.g.,wherein values of G″ and G′ are each individually in accordance with anyof the respective embodiments described herein) in a range of from 0.02to 1, at a temperature of 10° C. and frequency of 0.1 Hz. In some suchembodiments, the loss tangent is in a range of from 0.05 to 1. In somesuch embodiments, the loss tangent is in a range of from 0.1 to 1. Insome such embodiments, the loss tangent is in a range of from 0.2 to 1.In some such embodiments, the loss tangent is in a range of from 0.3to 1. In some such embodiments, the loss tangent is in a range of from0.5 to 1.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) in a rangeof from 0.01 to 1 (according to any of the respective embodimentsdescribed herein), and a shear storage modulus (G′) in a range of from0.01 to 10 MPa (according to any of the respective embodiments describedherein), at a temperature of 10° C. and frequency of 0.1 Hz. In somesuch embodiments, the shear storage modulus is in a range of from 0.05to 10 MPa. In some such embodiments, the shear storage modulus is in arange of from 0.1 to 5 MPa. In some such embodiments, the shear storagemodulus is in a range of from 0.2 to 2.5 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) in a rangeof from 0.05 to 0.7 (according to any of the respective embodimentsdescribed herein), and a shear storage modulus (G′) in a range of from0.01 to 10 MPa (according to any of the respective embodiments describedherein), at a temperature of 10° C. and frequency of 0.1 Hz. In somesuch embodiments, the shear storage modulus is in a range of from 0.05to 10 MPa. In some such embodiments, the shear storage modulus is in arange of from 0.1 to 5 MPa. In some such embodiments, the shear storagemodulus is in a range of from 0.2 to 2.5 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) in a rangeof from 0.175 to 0.5 (according to any of the respective embodimentsdescribed herein), and a shear storage modulus (G′) in a range of from0.01 to 10 MPa (according to any of the respective embodiments describedherein), at a temperature of 10° C. and frequency of 0.1 Hz. In somesuch embodiments, the shear storage modulus is in a range of from 0.05to 10 MPa. In some such embodiments, the shear storage modulus is in arange of from 0.1 to 5 MPa. In some such embodiments, the shear storagemodulus is in a range of from 0.2 to 2.5 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) in a rangeof from 0.01 to 1 (according to any of the respective embodimentsdescribed herein), and a shear loss modulus (G″) in a range of from0.0001 to 2 MPa (according to any of the respective embodimentsdescribed herein), at a temperature of 10° C. and frequency of 0.1 Hz.In some such embodiments, the shear loss modulus is in a range of from0.0003 to 0.3 MPa. In some such embodiments, the shear loss modulus isin a range of from 0.001 to 0.1 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.003 to 0.03 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) in a rangeof from 0.05 to 0.7 (according to any of the respective embodimentsdescribed herein), and a shear loss modulus (G″) in a range of from0.0001 to 2 MPa (according to any of the respective embodimentsdescribed herein), at a temperature of 10° C. and frequency of 0.1 Hz.In some such embodiments, the shear loss modulus is in a range of from0.0003 to 0.3 MPa. In some such embodiments, the shear loss modulus isin a range of from 0.001 to 0.1 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.003 to 0.03 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) in a rangeof from 0.175 to 0.5 (according to any of the respective embodimentsdescribed herein), and a shear loss modulus (G″) in a range of from0.0001 to 2 MPa (according to any of the respective embodimentsdescribed herein), at a temperature of 10° C. and frequency of 0.1 Hz.In some such embodiments, the shear loss modulus is in a range of from0.0003 to 0.3 MPa. In some such embodiments, the shear loss modulus isin a range of from 0.001 to 0.1 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.003 to 0.03 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear storage modulus (G′) in arange of from 0.01 to 10 MPa (according to any of the respectiveembodiments described herein), and a shear loss modulus (G″) in a rangeof from 0.0001 to 2 MPa (according to any of the respective embodimentsdescribed herein), at a temperature of 10° C. and frequency of 0.1 Hz.In some such embodiments, the shear loss modulus is in a range of from0.0003 to 0.3 MPa. In some such embodiments, the shear loss modulus isin a range of from 0.001 to 0.1 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.003 to 0.03 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear storage modulus (G′) in arange of from 0.05 to 10 MPa (according to any of the respectiveembodiments described herein), and a shear loss modulus (G″) in a rangeof from 0.0001 to 2 MPa (according to any of the respective embodimentsdescribed herein), at a temperature of 10° C. and frequency of 0.1 Hz.In some such embodiments, the shear loss modulus is in a range of from0.0003 to 0.3 MPa. In some such embodiments, the shear loss modulus isin a range of from 0.001 to 0.1 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.003 to 0.03 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear storage modulus (G′) in arange of from 0.1 to 5 MPa (according to any of the respectiveembodiments described herein), and a shear loss modulus (G″) in a rangeof from 0.0001 to 2 MPa (according to any of the respective embodimentsdescribed herein), at a temperature of 10° C. and frequency of 0.1 Hz.In some such embodiments, the shear loss modulus is in a range of from0.0003 to 0.3 MPa. In some such embodiments, the shear loss modulus isin a range of from 0.001 to 0.1 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.003 to 0.03 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a shear storage modulus (G′) in arange of from 0.2 to 2.5 MPa (according to any of the respectiveembodiments described herein), and a shear loss modulus (G″) in a rangeof from 0.0001 to 2 MPa (according to any of the respective embodimentsdescribed herein), at a temperature of 10° C. and frequency of 0.1 Hz.In some such embodiments, the shear loss modulus is in a range of from0.0003 to 0.3 MPa. In some such embodiments, the shear loss modulus isin a range of from 0.001 to 0.1 MPa. In some such embodiments, the shearloss modulus is in a range of from 0.003 to 0.03 MPa.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) which is atleast 200% of (two-fold) a loss tangent of the elastic layers (accordingto any of the respective embodiments described herein), at a frequencyof 0.1 Hz, and at any temperature within the range of from 0 to 40° C.In some such embodiments, the temperature is 37° C. In some suchembodiments, the temperature is 25° C. In some such embodiments, thetemperature is 20° C. In some such embodiments, the temperature is 0° C.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) which is atleast 300% of (3-fold) a loss tangent of the elastic layers (accordingto any of the respective embodiments described herein), at a frequencyof 0.1 Hz, and at any temperature within the range of from 0 to 40° C.In some such embodiments, the temperature is 37° C. In some suchembodiments, the temperature is 25° C. In some such embodiments, thetemperature is 20° C. In some such embodiments, the temperature is 0° C.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) which is atleast 500% of (5-fold) a loss tangent of the elastic layers (accordingto any of the respective embodiments described herein), at a frequencyof 0.1 Hz, and at any temperature within the range of from 0 to 40° C.In some such embodiments, the temperature is 37° C. In some suchembodiments, the temperature is 25° C. In some such embodiments, thetemperature is 20° C. In some such embodiments, the temperature is 0° C.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) which is atleast 1,000% of (10-fold) a tangent of the elastic layers (according toany of the respective embodiments described herein), at a frequency of0.1 Hz, and at any temperature within the range of from 0 to 40° C. Insome such embodiments, the temperature is 37° C. In some suchembodiments, the temperature is 25° C. In some such embodiments, thetemperature is 20° C. In some such embodiments, the temperature is 0° C.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) which is atleast 3,000% of (30-fold) a loss tangent of the elastic layers(according to any of the respective embodiments described herein), at afrequency of 0.1 Hz, and at any temperature within the range of from 0to 40° C. In some such embodiments, the temperature is 37° C. In somesuch embodiments, the temperature is 25° C. In some such embodiments,the temperature is 20° C. In some such embodiments, the temperature is0° C.

In some embodiments of any one of the embodiments described herein, aviscoelastic layer (according to any of the respective embodimentsdescribed herein) is characterized by a loss tangent (G″/G′) which is atleast 10,000% of (100-fold) a loss tangent of the elastic layers(according to any of the respective embodiments described herein), at afrequency of 0.1 Hz, and at any temperature within the range of from 0to 40° C. In some such embodiments, the temperature is 37° C. In somesuch embodiments, the temperature is 25° C. In some such embodiments,the temperature is 20° C. In some such embodiments, the temperature is0° C.

Without being bound by any particular theory, it is believed that a corematrix wherein the viscoelastic layer has a considerably higher losstangent (and accordingly, a less solid behavior) than the elastic layersmay undergo an elastic deformation in which the viscoelastic polymericmaterial may concomitantly undergo non-elastic deformation and viscousflow within the core matrix, while the matrix retains elastic propertiesdue to the elastic properties of the elastic layers.

Preparation:

Any of the fibers described herein (according to any one of therespective embodiments) may optionally be produced by any suitabletechnique for preparing fibers (including macro-sized fibers,micro-sized fibers and nano-sized fibers), such as conventionalfiber-spinning techniques. Such techniques include, for example,solution spinning, electrospinning, wet spinning, dry spinning, meltspinning and gel spinning. Each spinning method imparts specificphysical dimensions and mechanical properties of the resulting fibers,and can be tuned to give the desired characteristics according to therequired application of the fibers and layer of fibers described herein.

Briefly, a fiber spinning technique optionally involves the use ofspinnerets. These are similar, in principle, to a bathroom shower head,and may have from one to several hundred small holes. As the filaments,or crude fibers, emerge from the holes in the spinneret, the dissolvedor liquefied polymer is converted first to a rubbery state and thensolidified. This process of extrusion and solidification of “endless”crude fibers is called spinning, not to be confused with the textileoperation of the same name, where short pieces of staple fiber aretwisted into yarn.

Wet spinning is used for fiber-forming substances that have beendissolved in a solvent. The spinnerets are submerged in a chemical bathand as the filaments emerge they precipitate from solution and solidify.Because the solution is extruded directly into the precipitating liquid,this process for making fibers is called wet spinning. Fibers such as,for example, acrylic, rayon, aramid, modacrylic and spandex can beproduced by this process.

Dry spinning is also used for fiber-forming substances in solution,however, instead of precipitating the polymer by dilution or chemicalreaction, solidification is achieved by evaporating the solvent in astream of air or inert gas. The filaments do not come in contact with aprecipitating liquid, eliminating the need for drying and easing solventrecovery. This process may be used for the production of, for example,acetate, triacetate, acrylic, modacrylic, PBI, spandex and vinylon.

In melt spinning, the fiber-forming substance is melted for extrusionthrough the spinneret and then the crude fibers directly solidified bycooling. Melt spun crude fibers can be extruded from the spinneret indifferent cross-sectional shapes (round, trilobal, pentagonal, octagonaland others). Nylon (polyamide), olefin, polyester, saran and sulfur, forexample, are produced in this manner. Non-polymeric fibers can also beproduced by melt-spinning.

Gel spinning is a special process used to obtain high strength or otherspecial fiber properties. The polymer is not in a true liquid stateduring extrusion. Not completely separated, as they would be in a truesolution, the polymer chains are bound together at various points inliquid crystal form. This produces strong inter-chain forces in theresulting filaments that can significantly increase the tensile strengthof the fibers. In addition, the liquid crystals are aligned along thefiber axis by the shear forces during extrusion. The filaments emergewith an unusually high degree of orientation relative to each otherwhich increases their strength. The process can also be described asdry-wet spinning, since the filaments first pass through air and thenare cooled further in a liquid bath. Some high-strength polyethylene andaramid fibers, for example, are produced by gel spinning.

Alternatively, the fibers can be of natural or synthetic origins, andcan be provided ready for use without further manipulation orpreparation procedures or upon surface treatment thereof.

In some embodiments of any one of the embodiments described herein, thefibers are formed of electrospun polymeric material.

As used herein, the terms “electrospin”, “electrospinning”,“electrospun” and the like refer to a technology which produces fibers(e.g., nanofibers) from a polymer solution. During this process, one ormore polymers of the polymeric material as described herein areliquefied (i.e., melted or dissolved) and placed in a dispenser. Anelectrostatic field is employed to generate a positively charged jetfrom the dispenser to the collector. Thus, a dispenser (e.g., a syringewith metallic needle) is typically connected to a source of highvoltage, preferably of positive polarity, while the collector isgrounded, thus forming an electrostatic field between the dispenser andthe collector. Alternatively, the dispenser can be grounded while thecollector is connected to a source of high voltage, preferably withnegative polarity. As will be appreciated by one ordinarily skilled inthe art, any of the above configurations establishes motion ofpositively charged jet from the dispenser to the collector. Reversepolarity for establishing motions of a negatively charged jet from thedispenser to the collector is also contemplated. At the criticalvoltage, the charge repulsion begins to overcome the surface tension ofthe liquid drop. The charged jets depart from the dispenser and travelwithin the electrostatic field towards the collector. Moving with highvelocity in the inter-electrode space, the jet stretches and the solventtherein evaporates, thus forming fibers which are collected on thecollector, e.g., in a form of a layer of fibers.

Several parameters may affect the diameter of the fiber, these include,the size of the dispensing hole of the dispenser, the dispensing rate,the strength of the electrostatic field, the distance between thedispenser and/or the concentration of the polymeric material used forfabricating the electro spun fiber.

The dispenser can be, for example, a syringe with a metal needle or abath provided with one or more capillary apertures from which theliquefied polymeric material as described herein can be extruded, e.g.,under the action of hydrostatic pressure, mechanical pressure, airpressure and high voltage.

According to one embodiment, the collector is a rotating collector whichserves for collecting the electrospun fibers thereupon. Employing arotating collector can result in a layer of electrospun fibers with acontinuous gradient of porosity. Such a porosity gradient can beachieved by continuous variation in the velocity of the collector or bya longitudinal motion of the dispenser, these result in a substantialvariation in the density and/or spatial distribution of the fibers onthe collector and thus, result in a porosity gradient along the radialdirection or along the longitudinal direction of the collector,respectively. Typically, but not obligatorily, the rotating collectorhas a cylindrical shape (e.g., a drum); however, it will be appreciatedthat the rotating collector can be also of a planar geometry.

According to another embodiment, the collector is a flat groundcollector which serves for collecting the electrospun scaffoldthereupon. Employing a flat ground collector enables collection ofrandom nanofibers. It will be appreciated that the flat ground collectoris typically a horizontal collector or a vertical collector.

In some embodiments of any one of the embodiments described herein, anytwo or more adjacent layers formed of fibers (including elastic layersand/or viscoelastic layers according to any of the respectiveembodiments described herein) are optionally prepared by continuouselectro spinning.

It is to be appreciated that a viscoelastic layer formed of fibers doesnot necessarily retain a fibrous structure. For example, as exemplifiedherein, a viscoelastic layer in a form of a continuous film may beformed from fibers which then merge, thereby losing some or all of theporous and fibrous nature of the layer.

According to an aspect of some embodiments of the invention, there isprovided a process of preparing a composition-of-matter and/or corematrix according to any of the respective embodiments described herein,the process comprising forming the one or more elastic layers (e.g.,made of polymeric fibers, according to any of the respective embodimentsdescribed herein) and the viscoelastic layer(s) by continuous electrospinning, thereby forming the composition-of-matter and/or core matrix.

According to an aspect of some embodiments of the invention, there isprovided a process of preparing a composition-of-matter and/or corematrix according to any of the respective embodiments described herein,the process providing the one or more elastic layers and theviscoelastic layer(s) (according to any of the respective embodimentsdescribed herein), placing the viscoelastic layer(s) parallel to theelastic layers (optionally between the elastic layers), e.g., in astacked formation, and pressing the elastic layers and the viscoelasticlayer(s) together, thereby forming the composition-of-matter and/or corematrix. In some such embodiments, the process further comprises formingthe elastic layers by electrospinning.

In some embodiments, pressing the elastic layers and viscoelasticlayer(s) together comprises applying a pressure of at least 1 gram/cm².In some embodiments, the pressure is at least 2 gram/cm². In someembodiments, the pressure is at least 4 gram/cm². In some embodiments,the pressure is at least 8 gram/cm².

In some embodiments, the process further comprises heating theviscoelastic layer prior to, concomitantly with, and/or subsequently topressing the layers. In some such embodiments, the heating is to atemperature which is above a glass transition temperature and/or meltingpoint (optionally a glass transition temperature) of a polymer in theviscoelastic layer, in accordance with any of the respective embodimentsdescribed herein (e.g., 40° C.).

Optional Applications:

According to another aspect of embodiments of the invention there isprovided an article-of-manufacture comprising a composition-of-matterand/or matrix according to any of the respective embodiments describedherein.

In some such embodiments, the article-of-manufacture consistsessentially of the composition-of-matter, as described herein.

In some such embodiments, the article-of-manufacture comprisesadditional components in addition the composition-of-matter, asdescribed herein.

Examples of articles-of-manufacture in which a flexiblecomposition-of-matter according to any of the respective embodimentsdescribed herein may be advantageously incorporated include, withoutlimitation, articles intended to be applied to surfaces of variousshapes, such as packaging materials, coatings, adhesive tape, sealants;articles comprising an inflatable component, such as a balloon (e.g.,balloon catheters); and devices with movable parts (wherein thecomposition-of-matter may optionally be attached to two or moreseparately movable parts), such as household and/or industrialmachinery.

In some embodiments of any one of the embodiments described herein, thearticle-of-manufacture is a medical device. In some such embodiments,the medical device is an implantable medical device.

In some embodiments of any one of embodiments described herein relatingto a medical device, the medical device is for use in the field ofgeneral surgery, neurology, ear-nose and throat, urology,gynecology/obstetrics, thoracic, dental/maxillofacial, gastroenterology,plastic surgery, ophthalmology, cardiovascular and/or orthopedicmedicine.

In some embodiments of any one of the embodiments described herein, thearticle-of-manufacture (e.g., medical device) is identified for use in atreatment. In some embodiments, the article-of-manufacture (e.g.,medical device) is identified for use in repairing and/or substituting abiological tissue.

According to another aspect of embodiments of the invention, there isprovided a method of repairing and/or substituting a biological tissuein a subject in need thereof, the method comprising contacting thebiological tissue with article-of-manufacture (e.g., medical device)described herein.

In some embodiments of any of the embodiments described herein relatingto repairing and/or substituting a biological tissue, a biologicaltissue to be repaired and/or substituted is a membrane (e.g., followingtraumatic injury, hernia and/or surgical incision of the membrane). Insome embodiments, the membrane to be repaired and/or substituted is duramater (e.g., following traumatic injury and/or surgical incision of thedura mater). In some embodiments, the article-of-manufacture has asheet-like geometry (e.g., as described herein) which mimics that of amembrane.

Examples of treatments for which an article-of-manufacture according tosuch embodiments may be used (e.g., by implantation and/or temporaryinternal or topical use) in a treatment or method described herein(according to any of the respective embodiments) include, withoutlimitation, repairing and/or substituting a biological tissue, such asdural repair, hernia repair, internal and/or topical wound closure, skinclosure and/or repair (e.g., as part of plastic surgery), supportinganother medical implant (such as in breast reconstruction surgery),sealing tissues and/or organs in order to contain bodily fluids and/orair (e.g., treating bile duct leakage), sealing an anastomosis,inhibition of post-surgical adhesions between tissues and promotion ofhemostasis (e.g., wherein the matrix is coated with thrombin and/orfibrinogen and/or fibrin); as well as administration of atherapeutically effective agent (e.g., by incorporating thetherapeutically effective agent in and/or on the core matrix, accordingto any of the embodiments described herein relating to inclusion of anadditional ingredient).

Examples of treatments for which an implantable medical device accordingto embodiments described herein may be identified for use include,without limitation, dural repair, hernia repair, internal wound closure,sealing tissues and/or organs in order to contain bodily fluids and/orair, sealing an anastomosis, inhibition of post-surgical adhesionsbetween tissues, promotion of hemostasis, and administration of atherapeutically effective agent.

In some embodiments of any of the embodiments described herein, themedical device is configured for eluting a therapeutically active agent,e.g., an agent included as an additional ingredient according to any ofthe respective embodiments described herein. In some such embodiments,the medical device is a stent. Optionally, the composition-of-matterforms at least a portion of a flexible sleeve of the stent.

The therapeutically active agent may optionally be incorporated within acore matrix and/or on a surface of the core matrix. Optionally, thetherapeutically active agent is incorporated within a drug-eluting layerwithin the core matrix and/or on a surface of the core matrix. Such adrug eluting layer may be formed of any suitable substance known in theart of drug-eluting layers.

Herein, the phrase “repairing and/or substituting a biological tissue”refers to repair of tissue which is physically damaged in any manner,and encompasses supporting and/or holding damaged tissue together invivo or ex vivo, as well as filling gaps formed by an absence of tissue(substituting tissue). The damaged tissue may be damaged, for example,by detachment (e.g., tearing, cutting), compressive stress, tensilestress, shear stress, cellular dysfunction and/or cell death.

In some embodiments of any of the embodiments described herein relatingto repairing and/or substituting a biological tissue, the repairingand/or substituting a biological tissue comprises suturing thearticle-of-manufacture to the tissue (that is, thearticle-of-manufacture and tissue are attached via at least one suture).

As exemplified herein, core matrices described herein are particularlysuitable for being sutured without losing mechanical or functionalintegrity.

As used herein the term “about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a polymer” or “at least one polymer” may include a pluralityof polymers, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in anon-limiting fashion.

Materials and Methods

Materials:

Dimethylformamide was obtained from Sigma Aldrich (Israel).

Dioxane was obtained from Sigma Aldrich (Israel).

Tetrahydrofuran was obtained from Sigma Aldrich (Israel).

Poly(ε-caprolactone-co-L-lactic acid-co-glycolic acid-co-trimethylenecarbonate) was obtained from/by Poly-Med Inc. (USA).

Poly(L-lactic acid) was obtained from NatureWorks (USA).

Poly(DL-lactic acid-co-ε-caprolactone) was obtained from Lactel (USA).

Poly(L-lactic acid-co-ε-caprolactone) was obtained from PuracBiomaterials (Netherlands).

Determination of Structure and Morphology:

Samples of individual sheets or 3-layer patches were coated with goldand characterized using a Quanta 200 environmental scanning electronmicroscope (SEM) with a tungsten filament (FET). Fiber size and meanpore size were measured using ImageJ software.

Mechanical Properties:

Tensile tests (strain ramp) were carried out using a custom-madeuniaxial tensile machine (equipped with a 25 kg load cell) in accordancewith ASTM international standard D882-12 for testing tensile propertiesof thin plastic sheeting. Patches were cut in a dog bone configurationand thickness was measured at three points along the neck of the dogbone. The samples were immersed in PBS (phosphate buffer saline) at atemperature of 37° C. for 15 minutes before the test, and then mountedon the clamps of the machine. Each sample was stretched until breakage.The sample's Young's modulus (elastic modulus), ultimate tensilestrength (UTS) and elongation at failure were determined.

Shear loss (G′) and shear storage (G″) modulus of the middle layer wereevaluated via shear rheometer. The measurements were conducted using astrain-controlled rotational rheometer (AR-G2, TA Instruments), with astainless steel parallel plate geometry (20 mm), which includes aPeltier temperature control. All tests were conducted at a temperatureof 10° C. A strain sweep and frequency sweep tests were conducted todetermine the linear viscoelastic regime of the layer. Time andtemperature sweep tests were then performed at a strain range of0.1-0.7% and a frequency of 0.05-1 Hz.

Suture Retention Test:

Suture retention tests were based on the method described in theANSI/AAMI/ISO 7198:1998/2001/(R) 2004 standard. Samples were cut andconditioned as described hereinabove for the uniaxial tensile test. Oneend of the dog bone shaped sample was removed by scalpel and the samplewas sutured (Premilene® 4/0 suture) at a minimum distance of 2 mm fromits free end. The sample was then placed on the tensile machine, byconnecting the patch to the first grip and the suture to the other grip.A tensile test was then conducted as described hereinabove, in order tomeasure the force at failure of the samples.

Statistical Methods:

All final values describe the average of a minimum of 3 test items.Results are expressed as the mean values±standard error.

Example 1

Electrospun Elastic Sheets

Particles of a polymer or polymer blend were dissolved in a 25:25:50(w/w) mixture of dimethylformamide:dioxane:tetrahydrofuran to form ahomogeneous solution with no aggregations. Electro spinning of thesolution was conducted as depicted in FIG. 1 , at a temperature of 25±5°C. and a relative humidity of 35±10%, using a syringe pump, a 22-gaugeneedle (inner diameter ˜0.413 mm) or 23-gauge needle (inner diameter˜0.337 mm), a solution flow rate of 2.5 or 3 ml/hour, a DC voltagesupply of 8 kV (±1 or 2 kV), and a tip-to-collector distance of 10±3 cm.Unwoven patches were collected on an aluminum vertical wheel (diameter1.7 cm, width of 4.5 cm) rotating at 400 rotations per minute. Theobtained sheets were dried from residual solvents by exposure to avacuum at room temperature for 12 hours.

The following polymers were electrospun using the above generalprocedure (molecular weights herein refer to weight average molecularweights, except when indicated otherwise)

PLLA—poly(L-lactic acid) homopolymer (molecular weight 150±5 kDa);

PLLA/CL—poly(L-lactic acid-co-ε-caprolactone) (molar ratio 70:30 lacticacid:caprolactone, molecular weight 210±10 kDa);

PCL/LLA/GA/TMC—poly(ε-caprolactone-co-L-lactic acid-co-glycolicacid-co-trimethylene carbonate) linear block copolymer (molar ratio35:34:17:14 caprolactone:lactic acid:glycolic acid:trimethylenecarbonate, molecular weight 165±5 kDa, number average molecular weight90±5 kDa);

Using the above general procedure and polymers, the following elasticsheets were prepared.

Example 1a

Electrospinning of a PLLA/CL solution (with a polymer concentration of15 weight percents) was performed using a solution flow rate of 2.5ml/hour and 23-gauge needle. The obtained sheets were 230±30 μm thick.

As shown in FIGS. 3A and 3B, the fibers of the sheet were smooth and hada circular cross section with a mean diameter of about 3 μm, and thepore size ranged from about 5-40 μm.

Example 1b

Electrospinning of a PLLA/CL solution (with a polymer concentration of15 weight percents) was performed using a solution flow rate of 3ml/hour and 22-gauge needle. The obtained sheets were 230±30 μm thick.

As shown in FIGS. 3C and 3D, the fibers of the sheet weremorphologically more variable, and the pore size (about 2-30 μm) wassomewhat smaller, as compared to Example 1a (FIGS. 3A and 3B).

Example 1c

Electrospinning of a PCL/LLA/GA/TMC solution (with a polymerconcentration of 10 weight percents) was performed with a solution flowrate of 2.5 ml/hour and 23-gauge needle. The obtained sheets were 50±20μm thick.

Example 1d

A solution of a blend of PLLA/CL and PLLA was prepared with a PLLA/CLconcentration of 14 weight percents and a PLLA concentration of 1.5weight percent, and electrospinning of the solution was performed usinga solution flow rate of 2.5 ml/hour and 23-gauge needle. The obtainedsheets were 160±20 μm thick.

Example 1e

A solution of a blend of PCL/LLA/GA/TMC and PLLA was prepared with aPCL/LLA/GA/TMC concentration of 10 weight percents and a PLLAconcentration of 2 weight percents, and electrospinning of the solutionwas performed using a solution flow rate of 2.5 ml/hour and 23-gaugeneedle. The obtained sheets were 120±20 μm thick.

Example 2

Viscoelastic Sheets Prepared by Film Casting or Electrospinning

Example 2a

A viscoelastic sheet was prepared by a film casting technique. Particlesof PDLA/CL (poly(DL-lactic acid-co-ε-caprolactone), molar ratio 25:75lactic acid:caprolactone, molecular weight 90.1 kDa, number averagemolecular weight 39.4 kDa) were dissolved in tetrahydrofuran to form ahomogeneous solution with no aggregations. The solution was then castedinto a 5×5 cm polytetrafluoroethylene mold and vacuum dried at roomtemperature for 12 hours to remove residual solvents. The thickness ofthe obtained film was approximately 35 μm, as determined via scanningelectron microscopy (SEM).

Example 2b

In an alternative procedure, viscoelastic sheets were prepared byelectrospinning. Particles of PDLA/CL (poly(DL-lacticacid-co-ε-caprolactone) as described hereinabove) were dissolved at aconcentration of 30 weight percents in a 25:25:50 (w/w) mixture ofdimethylformamide:dioxane:tetrahydrofuran to form a homogeneous solutionwith no aggregations. Electrospinning of the solution was conducted at atemperature of 25±5° C. and a relative humidity of 35±10%, using asyringe pump, a 21-gauge needle (inner diameter ˜0.51 mm), a solutionflow rate of 2.5 ml/hour, a DC voltage supply of 8±1 kV, and atip-to-collector distance of 10±3 cm. Unwoven patches were collected onan aluminum vertical wheel (diameter 1.7 cm, width of 4.5 cm) rotatingat 400 rotations per minute. The obtained sheets were dried fromresidual solvents by exposure to a vacuum at room temperature for 12hours. During this time, the fibers merged to form a film which appearedhomogeneous under a light microscope.

Relatively thin sheets, characterized by thicknesses in a range of about15-30 μm, were obtained by electrospinning 1 ml of the solution.Moderately thicker sheets, characterized by thicknesses in a range ofabout 40-60 μm, were obtained by electrospinning 2 ml of the solution.The thicknesses of the sheets were determined via scanning electronmicroscopy (SEM).

Example 2c

A viscoelastic sheet was prepared by electrospinning as described inExample 2b, except that the solution was prepared by dissolvingparticles of PDLA/CL (poly(DL-lactic acid-co-ε-caprolactone) asdescribed hereinabove) and PLLA/CL (poly(L-lacticacid-co-ε-caprolactone) as described hereinabove) at a concentration of30 weight percents PDLA/CL and 0.5 weight percent PLLA/CL. The thicknessof the obtained film was approximately 30 μm, as determined via SEM.

Example 3

Integral 3-Layer Patch Prepared by Continuous Electrospinning

An integral 3-layer patch, comprising a viscoelastic layer sandwichedbetween two elastic layers (as depicted in FIG. 2 ), was prepared bycontinuous electrospinning. An elastic first layer comprising PLLA/CLfibers was produced as described in Example 1a. A viscoelastic secondlayer (middle layer) comprising PDLA/CL was then prepared as describedin Example 2b by direct electrospinning, and collected on the firstlayer. An elastic third layer comprising PLLA/CL fibers was produced asdescribed in Example 1a, and collected above the first and secondlayers. The obtained patch was vacuum dried at room temperature for 12hours.

As shown in FIGS. 4A and 4B, the thickness of the obtained patch wasapproximately 550 μm, with the thickness of the middle layer being 25±5μm, and the thickness of each of the elastic external layers (the firstand third layers) being 230±30 μm, as determined via scanning electronmicroscopy (SEM).

As further shown therein, the viscoelastic middle layer retained afibrous structure, although some merging of fibers due to diffusion ofthe polymer is observable.

In alternative procedures, the elastic first layer and/or third layer isprepared as described in any one of Examples 1b, 1c, 1d and 1e, ratherthan Example 1a.

Example 4

Integral 3-Layer Patch Prepared by Layer-by-Layer Technique

An integral 3-layer patch, comprising a viscoelastic layer sandwichedbetween two elastic layers (as depicted in FIG. 2 ), was prepared byplacing a viscoelastic sheet prepared as described in Example 2 betweentwo elastic sheets prepared as described in Example 1. The 3 sheets wereheated at temperature of 40° C. for 5 minutes, and then pressed togetherusing a pressure of 8 grams/cm². The heat increased the mobility of thepolymer in the viscoelastic layer, facilitating its diffusion into thepores of the elastic layers.

Using the above general procedure, the following 3-layer patches wereprepared.

Example 4a

A viscoelastic sheet comprising PDLA/CL was prepared by electrospinning1 ml of solution as described in Example 2b, and sandwiched between twoelectrospun elastic sheets comprising electrospun PLLA/CL, which wereprepared as described in Example 1a. The obtained patch wasapproximately 500 μm thick, as determined by scanning electronmicroscopy (SEM).

As shown in FIGS. 5A and 5B, a suture hole in the patch created by a 4-0Monocryl® suture (Ethicon) was substantially closed by the elasticity ofthe elastic layer.

Similarly, as shown in FIGS. 5C and 5D, the elastic layer closed tightlyaround a polypropylene monofilament 4/0 (Premilene®) suture (FIG. 5C)and poly(glycolic acid) braided 4/0 suture (FIG. 5D) left in place.

As shown in FIGS. 5E and 5F, the structure of the elastic layer wascharacterized by distinct fibers, whereas the viscoelastic layer formeda continuous film (with a thickness of about 25 μm) due to merging ofthe fibers therein.

As further shown in FIG. 5F, the polymer of the viscoelastic layerpartially diffused into the elastic layer (probably during theapplication of pressure and heat).

An additional patch was prepared using a viscoelastic sheet prepared asdescribed in Example 2b, with twice as much polymer solution (2 mlinstead of 1 ml).

As shown in FIGS. 6A-6C, the viscoelastic layer prepared with 2 mlpolymer solution was characterized by a thickness of about 50 μm, ascompared with 25 μm the viscoelastic layer prepared with 1 ml polymersolution (as shown in FIGS. 5E and 5F).

In order to determine the ability of the patches to retain sutures, asuture retention test was performed as described in the Materials andMethods section hereinabove.

The mean force applied to a suture in a 3-layer patch until failure ofthe patch was 237.8±8.7 grams force. This result indicates that asutured 3-layer patch exhibits satisfactory mechanical strength andability to retain sutures.

Example 4b

A viscoelastic sheet comprising electrospun PDLA/CL and PLLA/CL wasprepared by electrospinning as described in Example 2c, and sandwichedbetween two electrospun elastic sheets comprising PLLA/CL, which wereprepared as described in Example 1a. The patch was then vacuum-dried for12 hours at room temperature. The obtained patch was approximately 525μm thick, as determined by SEM.

Example 4c

A viscoelastic sheet comprising PDLA/CL was prepared by film casting asdescribed in Example 2a, and sandwiched between two electrospun elasticsheets comprising PLLA/CL, which were prepared as described in Example1a. The obtained patch was approximately 490 μm thick, as determined bySEM.

In alternative procedures, using the above general procedure, aviscoelastic sheet prepared according to any one of Examples 2a, 3b and2c is sandwiched between two elastic sheets prepared as described in anyone of Examples 1b, 1c, 1d and 1e, rather than Example 1a.

Example 5

Mechanical Properties of Layers and 3-Layer Patches

The Young's modulus at strains of 50-125% (10-25 mm extension), ultimatetensile strength and elongation at failure were determined forsingle-layer elastic sheets prepared as described in each of Examples1a-1e, and for 3-layered patches prepared as described in each ofExamples 3-4c, using procedures described in the Materials and Methodssection hereinabove. The results are presented in Table 1 below.

TABLE 1 Mechanical properties of single-layer elastic sheets and 3-layerpatches (mean ± standard deviation of 3 measurements per sample) ExampleNo. Elastic sheets 3-layer patches (Example 1) (Examples 3 & 4) 1a 1b 1c1d 1e 3 4a 4b 4c Young's 0.25 ± 0.04 0.32 ± 0.05 0.74 ± 0.14 0.715 ±0.09  0.762 ± 0.09  0.35 ± 0.1  0.22 ± 0.05 0.194 ± 0.05  0.11 ± 0.02modulus [MPa] UTS  5.3 ± 0.18  6.3 ± 0.28  6.8 ± 0.84  5.3 ± 0.73  5.0 ±0.34  5.3 ± 0.46 4.6 ± 1.3  3.6 ± 1.02  4.5 ± 0.91 [MPa] Elongation 386± 9  342 ± 22  493 ± 32  261 ± 31  407 ± 34  439 ± 24  507 ± 66  541 ±106 449 ± 27  [%]

As shown in Table 1, all of the samples exhibited low Young's modulusvalues, indicating an ability to readily undergo deformation immediatelyupon loading, as well as an ability to undergo considerable elongation(about 250-550%) before breaking. As further shown therein, themechanical properties of the 3-layer patches were similar to those ofthe elastic sheets incorporated within the patches (the elastic sheet ofExample 1a).

These results indicate that the elastic layers and patches containingthem exhibit mechanical properties similar to those of some biologicalfibers, such as elastin and resilin, which exhibit a Young's modulus onthe order of a few MPa and elongation of above 100%.

In order to evaluate the properties of the viscoelastic layer, the shearstorage modulus (G′) and shear loss modulus (G″) of a viscoelastic sheetprepared as described in Example 2a were determined by oscillatory sheartests, as described in the Materials and Methods section hereinabove.The ratio of G″ to G′ can be expressed as the loss tangent (G″/G′) or asthe phase angle (arctangent of G″/G′), wherein a relatively high losstangent (and phase angle approaching 90°) indicates viscous, liquid-likeproperties, whereas a relatively low loss tangent (and phase angleapproaching 0°) indicates more elastic and solid-like properties.

The viscoelastic layers exhibited a phase angle in a range of from 10.2°to 25.87°, corresponding to a loss tangent in a range of from 0.180 to0.485.

These results indicate that the viscoelastic layers exhibit gel-likebehavior, wherein there is a significant degree of viscous, liquid-likebehavior, but elastic, solid-like properties predominate (e.g., G′>G″).

Example 6

Water-Permeability of Layers and 3-Layer Patches

In order to evaluate the water-permeability of 3-layered patchesprepared as described herein, as well as the effect of each layer onwater-permeability, the water-permeability of the following materialswas tested:

-   -   1) an electrospun elastic sheet prepared as described in Example        1a;    -   2) a double elastic layer, prepared by pressing together two        electrospun elastic sheets (prepared as described in Example 1a)        according to the procedures described in Example 4, but without        a viscoelastic middle layer;    -   3) a 3-layer patch prepared by continuous electrospinning, as        described in Example 3;    -   4) a 3-layer patch prepared by pressing together from 3 sheets,        as described in Example 4a;    -   5) a 3-layer patch as described in Example 4a, sutured once        using a poly(glycolic acid) 4/0 suture and a 19 mm ⅜ needle, the        suture remaining in the patch;    -   6) a 3.5 mm thick Duragen™ suturable collagen dural substitute        (Integra), for comparison.

Testing was performed in accordance with ISO 811, with severalmodifications. Test items were inserted into a custom-made testingapparatus made of Plexiglas®. The apparatus was comprised of an inlettube (inner diameter 1.7 cm) filled with saline at 37° C., to thedesired height. The test item was placed at the bottom of the inlettube, and was held in place by two rubber rings with an inner diameterequal to that of the tube. Saline was added to the inlet tube such thatthe surface area of the test item exposed to the saline was 9 cm².During testing, the apparatus was maintained at a steady temperature of37° C. The amount of saline that passed the item into the outlet tubewas measured during the course of 30 minutes. To verify a constantpressure the level of fluid in the tube was kept constant. The degree ofwater-permeability was determined by comparing the amount of saline thatpassed the items into the outlet tube. Two levels of pressures weretested: 1) 15 mmHg, which corresponds to the normal intracranial CSFpressure; and 2) 40 mmHg, which corresponds to higher than normalintracranial pressure.

As shown in FIG. 7 , the single elastic layers, and to a lesser extent,the double elastic layers, exhibited some leakage which was correlatedwith pressure, whereas the 3-layer patches prepared as described inExample 4a exhibited no leakage at either tested pressure.

These results indicate that the viscoelastic middle layer provided ahigh degree of water-impermeability, whereas the elastic layers areporous and somewhat water-permeable.

As further shown in FIG. 7 , the 3-layer patches prepared as describedin Example 3 were considerably more water-impermeable than the single ordouble elastic layer, but exhibited slight leakage. This result is inaccordance with the above-described finding that the viscoelastic layerin these 3-layer patches retained a partially porous fibrous structure,in contrast to the more continuous structure of the viscoelastic layerin 3-layer patches prepared as described in Example 4a.

As further shown therein, the presence of a suture in a 3-layer patchdid not result in leakage at relatively low pressure (15 mmHg), andresulted in only a very small degree of leakage at higher pressure (40mmHg).

These results suggest that the patch effectively closes tightly aroundthe suture, thereby minimizing leakage at the location of the suture.

As further shown in FIG. 7 , the collagen dural substitute exhibited thehighest rate of leakage by far, despite being the thickest materialtested. The entire column of saline leaked through the collagen duralsubstitute within less than 5 minutes.

This result indicates that the elastic layers in a patch are alsorelatively water-impermeable, in comparison with a collagen duralsubstitute.

Example 7

Layered Patches with Tissue-Interactive Additives

A patch comprising one or more additives is prepared using a core matrixcomprising elastic layers and a viscoelastic layer, corresponding to a3-layer patch as described in any one of Examples 3 and 4, and one ormore additives on a surface of the core matrix, such that additive(s)can directly contact tissue onto which the patch is applied. Theadditive(s) is selected to be adhesive, thereby allowing the patch toadhere to tissue without sutures, and/or selected to facilitate cellattachment and/or proliferation on the patch surface. The core matrixprovides the patch with water-impermeability and mechanical strength andresilience.

An additive is optionally a substance applied onto the core matrix andoptionally a product of surface modification of the core matrix.

An additive selected to be adhesive is optionally a surface modificationtechnique such as plasma surface treatment (optionally with oxygenplasma, ammonia plasma, argon plasma or air plasma), exposure to flames,mechanical treatment, corona discharge, wet-chemical treatment and/orsurface grafting (e.g., of monomers or polymers, optionallypoly(N-isopropylacrylamide), poly(acrylic acid) and/or poly(aminoacids)).

The surface modification (e.g., plasma surface treatment, surfacegrafting) optionally increases the hydrophilicity of a surface of thepatch by altering the electrostatic charge of the surface.

An additive selected to be adhesive is optionally an adhesive substance(e.g., synthetic or biological in origin) in dry form, which is appliedby coating at least a portion of the surface of the core matrix with theadhesive additive. The adhesiveness of the substance is enhanced uponhydration, for example, upon contact with moist tissue. The adhesiveadditive is optionally a dry combination of thrombin and fibrinogen(which interact upon hydration to form fibrin), an albumin coating(optionally formed by electrospinning), and/or a polymer (optionally apolysaccharide, poly(vinyl acetate) and/or poly(vinyl pyrrolidone))which includes a functional group (optionally an imido ester,p-nitrophenyl carbonate, N-hydroxysuccinimide (NHS) ester, epoxide,isocyanate, acrylate, vinyl sulfone, orthopyridyl-disulfide, maleimide,aldehyde and/or iodoacetamide group) that can react with a surfaceprotein to form a covalent bond.

The amount of adhesive is optionally controlled such that the adhesionstrength of the patch (as evaluated by the lap shear strength of a patchadhered to a biological fascia measured by a uniaxial tensile test) isin a range of from 10 to 30 kPa.

An additive selected to facilitate cell attachment and/or proliferationis optionally a coating of growth factors and/or a layer (optionallyhaving a thickness in a range of from 50 to 400 μm) of biocompatiblenanofibers, optionally formed by electrospinning. The nanofibers areoptionally composed of synthetic polymers and/or co-polymers (e.g.polyesters) and/or biological polymers (e.g., gelatin, collagen,elastin, laminin and/or fibronectin).

Example 8

Layered Patches with Anti-Adhesive Additives

A patch comprising one or more additives is prepared using a core matrixcomprising elastic layers and a viscoelastic layer, corresponding to a3-layer patch as described in any one of Examples 3 and 4, and one ormore additives on a surface of the core matrix, such that additive(s)can directly contact tissue onto which the patch is applied. Theadditive(s) is selected to reduce undesirable tissue adhesion to thepatch surface. The core matrix provides the patch withwater-impermeability and mechanical strength and resilience.

The additive(s) is in a form of a layer (optionally having a thicknessin a range of from 10 to 400 μm) of nanofibers (e.g., which exhibitanti-fouling properties), optionally formed by electrospinning. Thenanofibers are optionally composed of poly(ethylene glycol) and/orco-polymers comprising poly(ethylene glycol).

Example 9

Use of Layered Patch as a Dural Substitute

A layered patch as described in any one of Examples 3, 4, 7 and 8 isused to prevent cerebrospinal fluid (CSF) leakage through a damaged duramater (e.g., damaged by trauma or surgery requiring breach of the duramater).

The patch is optionally positioned between the dura mater and neuraltissue (e.g., brain) such that it overlays edges of a breached duramater, covering the breach in the dura mater.

Optionally, the patch comprises one or more additive selected to beadhesive and/or to facilitate cell attachment and/or proliferation onthe patch surface, as described in Example 7, on a surface which ispositioned adjacent to the dura mater and/or skull (e.g., on the side ofthe patch which faces away from the brain), thereby preferentiallyadhering to and/or facilitating cell attachment and/or proliferation inthe dura mater and/or tissue adjacent to the skull, rather than inneural tissue (e.g., the brain).

Additionally or alternatively, the patch comprises one or moreanti-adhesive additive as described in Example 8, on a surface which ispositioned adjacent to the neural tissue (e.g., on the side of the patchwhich faces towards the brain), thereby reducing and optionallypreventing adhesion of the patch to neural tissue.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

The invention claimed is:
 1. A composition-of-matter comprising amulti-layer matrix, said matrix comprising at least one layer of aviscoelastic polymeric material interposed between two or more layers ofan elastic polymeric material, wherein: each of said two or more layersof said elastic polymeric material is in a form of a porous layer ofpolymeric fibers; said viscoelastic polymeric material is characterizedby at least one of: (i) a glass transition temperature below 0° C., and(ii) a melting point at a temperature below 45° C.; said polymericfibers comprise poly(lactic acid-co-ε-caprolactone); and saidviscoelastic polymeric material comprises poly(lacticacid-co-ε-caprolactone).
 2. The composition-of-matter of claim 1,wherein each layer of said elastic polymeric material is a porous layercharacterized by a porosity of at least 50%.
 3. Thecomposition-of-matter of claim 1, wherein said polymeric fibers arecharacterized by a mean diameter in a range of from 0.5 to 10 μm.
 4. Thecomposition-of-matter of claim 1, wherein said layer of a viscoelasticpolymeric material is characterized by at least one of: a) a storageshear modulus (G′) in a range of from 0.01 to 10 MPa, at a temperatureof 10° C. and frequency of 0.1 Hz; b) a loss shear modulus (G″) in arange of from 0.0001 to 2 MPa, at a temperature of 10° C. and frequencyof 0.1 Hz; and c) a loss tangent (G″/G′) at a temperature of 10° C. andfrequency of 0.1 Hz which is in a range of from 0.01 to
 4. 5. Thecomposition-of-matter of claim 1, wherein polymeric fibers compriseelectrospun elastic polymeric material.
 6. The composition-of-matter ofclaim 1, wherein said layer of a viscoelastic polymeric material ischaracterized by a porosity in a range of from 0 to 50%.
 7. Thecomposition-of-matter of claim 1, wherein said elastic polymericmaterial and said viscoelastic polymeric material are biocompatible. 8.The composition-of-matter of claim 1, wherein said matrix ischaracterized by a thickness of between 0.06 and 1 mm.
 9. Thecomposition-of-matter of claim 1, wherein each of said layers of anelastic polymeric material is characterized by an elastic modulus in arange of from 1 kPa to 10 MPa, as determined in accordance with ASTMinternational standard D882-12.
 10. The composition-of-matter of claim1, wherein each of said layers of an elastic polymeric material ischaracterized by an elongation at failure of at least 100%.
 11. Thecomposition-of-matter of claim 1, wherein each of said layers of anelastic polymeric material is characterized by an ultimate tensilestrength (UTS) of at least 0.05 MPa, when measured according to ASTMinternational standard D882-12.
 12. The composition-of-matter of claim1, wherein said matrix is characterized by an elastic modulus which iswithin a range of 80% to 120% of an elastic modulus of at least one ofsaid elastic layers.
 13. The composition-of-matter of claim 1, whereinsaid matrix is characterized by UTS between above 4 MPa, when measuredaccording to ASTM international standard D882-12.
 14. Thecomposition-of-matter of claim 1, wherein said matrix is characterizedby a water-permeability of less than 1 ml per hour per cm² upon exposureto an aqueous liquid at a pressure of 40 mmHg.
 15. Thecomposition-of-matter of claim 1, further comprising at least oneadditional ingredient, said additional ingredient being in a form of anadditional layer on at least a portion of at least one surface of saidmatrix and/or dispersed within and/or on at least one surface of saidmatrix, said at least one additional ingredient imparting an additionalfunctionality.
 16. The composition-of-matter of claim 1, characterizedby self-recovery upon suturing or stapling.
 17. Thecomposition-of-matter of claim 1, wherein said matrix is characterizedby elastic modulus of about 1 MPa, when measured according to ASTMinternational standard D882-12 at 100% strain.
 18. Anarticle-of-manufacture comprising the composition-of-matter of claim 1,wherein the article-of-manufacture is a medical device.